Neuro-attenuating ketamine and norketamine compounds, derivatives thereof, and methods

ABSTRACT

The present invention is directed to novel neuro-attenuating norketamine (NANKET) compounds according to any one of formulas (I—shown below), (I-A) and (I-B), or any of the compounds described in Tables A-D, or in any of the Examples provided herein, and pharmaceutically acceptable salts thereof, novel pharmaceutical formulations and novel methods of uses thereof. The present invention also features novel oral neuro-attenuating ketamine (NAKET) and neuro-attenuating norketamine (NANKET) modified-release pharmaceutical formulations, and novel methods of administration thereof, which ensure the steady release of a therapeutically effective amount of ketamine, norketamine, or derivatives thereof from the oral modified-release pharmaceutical formulations without neurologically toxic spikes in plasma concentration of the ketamine, norketamine, or derivatives during the release periods.

I. CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/196,986, filed Mar. 9, 2021, which is a continuation of U.S. patentapplication Ser. No. 16/271,767, filed Feb. 8, 2019, which is acontinuation of U.S. patent application Ser. No. 15/524,224, filed May3, 2017, which is a national phase under 35 U.S.C. § 371, ofInternational Application Number PCT/US2015/059113, filed Nov. 4, 2015,which claims priority to U.S. Provisional Application No. 62/074,645,filed on Nov. 4, 2014, the entire contents of each of which are herebyincorporated by reference.

II. BACKGROUND

Ketamine is a non-selective N-methyl-d-aspartate (NMDA) receptorantagonist that has been approved by FDA for induction and maintenanceof the general anesthesia. It has also been shown effective in treatingother conditions, for example, to alleviate different kinds of pain(Correll, 2003), depression (Zarate, 2012), acute brain injury andstroke (Hertle, 2012), epilepsy (Synowiec, 2013), alcohol dependence,Alzheimer's disease, asthma and other disorders.

The oral efficacy of ketamine for treatment of pain has been confirmedby multiple investigators and recently reviewed (Blonk, 2010). In mostcases, ketamine was used as an oral solution prepared from thecommercially available injectable formulation (1 or 10% ketamine inwater), often times mixed with fruit juice or syrup for taste masking.Solid dose forms of ketamine have also been reported in severalexamples. In particular, Yanagihara et al. (Yanagihara 1999, 2003)reported preparation of oral tablets of ketamine by dry and wetgranulation with pharmacokinetics in humans similar to the orallyadministered syrup formulation. Furthermore, oral and sublingualformulations of ketamine as gelatin-based lozenges having a total weightof 1 g and ketamine load of 25 mg have also been prepared by Chong(Chong, 2009).

When administered orally, ketamine is a subject to the first-pass livermetabolism via N-demethylation and conversion to the active metaboliteNorketamine. The elimination half-life of ketamine has been estimated at2-3 hours, and 4 hours for norketamine. Consequently, the therapeuticwindow of orally administered ketamine is relatively short, and promptsan oral administration of multiple daily doses of the drug, e.g., 3-5times a day, to achieve desirable therapeutic effect.

Moreover, solid dose forms of ketamine have been consistently limited bytheir inability to provide therapeutically effective doses, even in theshort-term, without neurologically toxic spikes in ketamineconcentration. In fact, exceeding an optimal efficacy plasmaconcentration of the drug (10-300 ng/ml) leads to more pronounced sideeffects, such as sedation, hallucination, dizziness, and/or nausea,which can not only have immediate repercussions, but also effecttreatment compliance.

In order to achieve the optimal therapeutic index, the most successfulroute of administration for maintaining the stable levels of the drug inthe system over longer periods of time appears to be by infusion(Correll, 2004). Such administration affords direct titration control ofthe manner of the administration, and enables eliminating the presenceof neurological side effects, e.g., resulting from psychotomimetic toxicplasma concentration spikes of ketamine. However, the process ofinfusion presents significant challenges in patient management, as wellas the cost of the procedure, being difficult to administer outside ofthe Intensive Care Units (ICU).

As such, there remains a need for efficient, more convenient, andcontrollable ketamine formulations that mimic the results of ketamineinfusion and afford no neurologically toxic (e.g., psychotomimetictoxic) plasma concentrations, and which address the identified gap inketamine treatment of conditions such as pain, depression, traumaticbrain injury, stroke, epilepsy, alcohol dependence, or Alzheimerdisease.

III. SUMMARY OF THE INVENTION

The present invention overcomes the above-mentioned disadvantages anddrawbacks associated with ketamine therapy and is directed to thediscovery of novel, isolated and/or substantially pure,isotopically-enriched, neuro-attenuating norketamine compounds, novelpharmaceutical compositions formulated therewith and methods of usethereof, for the (i) treatment of a subject diagnosed with, sufferingfrom or susceptible to, (ii) prevention and/or (iii) management of adisease, disorder or condition, such as those for which ketaminetreatment may be considered, indicated, tried or recommended, includingpain, depression, anxiety, traumatic brain injury, stroke, migraines,epilepsy, schizophrenia, asthma, post traumatic disorder, bipolardisorder, alcohol dependence, Alzheimer disease, suicidality, autism,diabetic neuropathy, tinnitus, levodopa-induced dyskinesia, speudobulbareffect, Bulbar function, and the like.

In accordance with the present invention, the novel, isolated and/orsubstantially pure, isotopically-enriched, neuro-attenuating norketaminecompounds may be formulated into pharmaceutical compositions suitablefor oral (immediate release and modified-release), parenteral, topical,rectal, vaginal, intranasal, inhalation or liquid administration, suchas oral dosage forms like pills (e.g., tablets, capsules, caplets,troaches, lozenges, caches, gelcaps, caps, pellets, boluses, pastilles,orally disintegrating tablets, sublingual tablets and buccal tablets),thin films, powders, granules, crystals, liquid solutions, syrups,emulsions and suspensions, topical dosage forms like pastes, creams,ointments, gels, liquids, sprays, skin patches, dermal patches, balms,salves and implants, ophthalmic and otic dosage forms, e.g., drops,suspensions, emulsions, creams and gels, vaginal rings and inserts,suppositories, inhalation dosage forms like aerosols, inhalers,nebulizers and vaporizers, and parenteral dosage forms like intradermal(ID), intramuscular (IM), intraosseous (IO), intraperitoneal (IP),intravenous (IV), caudal, intrathecal (ITH), subcutaneous (SC), and thelike.

Also in accordance with the present invention, the novel, isolatedand/or substantially pure, isotopically-enriched, neuro-attenuatingnorketamine compounds and the novel pharmaceutical compositionsformulated therewith are suitable to (i) treat a subject for anyindication for which ketamine treatment may be considered, tried,indicated or recommended, whether or not the ketamine indication is anFDA-approved indication or an off-label indication, and/or (ii) preventand/or manage any disease, disorder or condition for which ketaminetreatment may be considered, tried, indicated or recommended, includingbut not limited to the treatment, prevention and/or management of anydisease, disorder or condition that concerns, for example, pain,depression, anxiety, traumatic brain injury, stroke, migraines,epilepsy, schizophrenia, asthma, post traumatic disorder, bipolardisorder, alcohol dependence, Alzheimer disease, suicidality, autism,diabetic neuropathy, tinnitus, levodopa-induced dyskinesia, speudobulbareffect, Bulbar function and the like.

The present invention is also directed to the discovery of novel, oral,modified-release neuro-attenuating ketamine (NAKET) and/orneuro-attenuating norketamine (NANKET) pharmaceutical formulations, andmethods of use thereof, for oral administrations, such as oralmodified-release tablet formulations, for providing improved therapeuticand safety profiles, as compared with existing compositions of oralketamine. In this regard, the novel oral neuro-attenuating ketamine(NAKET) and/or neuro-attenuating norketamine (NANKET) pharmaceuticalformulations are uniquely designed to ensure the steady release oftherapeutically effective amounts of a NAKET compound, e.g., ketamineand/or any compound of Formula II, and/or a NANKET compound, e.g.,norketamine, any compound of Formula I, (I-A), (I-B) and/or any of thecompounds described in Tables A-D, from the novel oral pharmaceuticalformulations for the duration of the release periods in a subjectfollowing an oral administration event. Quite surprisingly, the novel,oral, modified-release neuro-attenuating ketamine (NAKET) and/orneuro-attenuating norketamine (NANKET) pharmaceutical formulations ofthe present invention accomplish this therapeutic effect, ascontemplated by the present invention, without causing neurologicallytoxic spikes in ketamine and/or norketamine plasma concentrations thatmay induce side-effects of, for example, sedation and/or psychotomimeiceffects, such as hallucination, dizziness, and nausea.

In addition, the present invention provides novel derivatives for use inthe formulations and methods of the present invention. In particularembodiments, the present invention provides oral pharmaceuticalformulations of NAKET compounds and/or NANKET compounds. In certainspecific embodiments, oral, modified-release pharmaceutical formulationsof the present invention, and methods of administration, provide uniquesteady administration of NAKET compounds and/or NANKET compounds to asubject during release periods of about 12 hours or greater, forexample, for about 24 hours or greater, for about 36 hours or greater,or for even about 48 hours or greater, after a single oraladministration event, to now provide safe and therapeutically effectiveoral treatments of subjects with NAKET compounds and/or NANKETcompounds, including ketamine and norketamine.

Accordingly, in one aspect of the present invention, it provides acompound of formula I:

wherein

X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, X₁₁, X₁₂, X₁₃, and X₁₄ are eachindependently selected from the group consisting of hydrogen anddeuterium, and wherein at least one of X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈,X₉, X₁₀, X₁₁, X₁₂, X₁₃, and X₁₄ is deuterium, or a salt thereof.

In another aspect, the present invention provides for a novelpharmaceutical formulation comprising a compound of formula I, (I-A),(I-B), and/or any of the compounds described in Tables A-D.

In yet another aspect, the present invention provides an orallyadministrable, modified-release pharmaceutical composition, e.g., amodified-release, single-layer tablet composition, such as amodified-release, single-layer tablet formulated with a matrixcomposition, comprising a therapeutically effective amount of aneuro-attenuating norketamine (NANKET) compound, including norketamine,any compound of Formula I, (I-A), (I-B) and/or any of the compoundsdescribed in Tables A-D.

In still another aspect of the present invention, it provides for anovel pharmaceutical formulation comprising a neuro-attenuating ketamine(NAKET) compound, including ketamine, represented by formula II:

wherein

X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, X₁₁, X₁₂, X₁₃, X₁₄, X₁₅, andX₁₆ are each independently selected from the group consisting ofhydrogen and deuterium, and wherein at least one of X₁, X₂, X₃, X₄, X₅,X₆, X₇, X₈, X₉, X₁₀, X₁₁, X₁₂, X₁₃, X₁₄, X₁₅, and X₁₁ is deuterium.

In another aspect of the present invention, it provides for an orallyadministrable, modified-release pharmaceutical composition, e.g., amodified-release, single-layer tablet composition, such as amodified-release, single-layer tablet formulated with a matrixcomposition, comprising a therapeutically effective amount of aneuro-attenuating ketamine (NAKET) compound, including ketamine and/orany compound of Formula II.

Like with the novel, isolated and/or substantially pure,isotopically-enriched, neuro-attenuating norketamine compounds, thenovel, oral, modified-release pharmaceutical compositions formulatedwith a neuro-attenuating ketamine (NAKET) compound and/or aneuro-attenuating norketamine (NANKET) compound, including norketamine,any compound of Formula I, (I-A), (I-B) and/or any of the compoundsdescribed in Tables A-D, are suitable to (1) treat a subject for anyindication for which ketamine treatment may be considered, tried,indicated or recommended, whether or not the ketamine indication is anFDA-approved indication or an off-label indication, and/or (2) preventand/or manage any disease, disorder or condition such as those for whichketamine treatment may be considered, tried, indicated or recommended.Thus, in another unique aspect, the present invention provides for amethod of treating a subject comprising the step of administering to asubject in need thereof an oral, modified-release pharmaceuticalcomposition of the present invention formulated with a therapeuticeffective amount of a neuro-attenuating ketamine (NAKET) compound,including ketamine and any compound of Formula II, and/or aneuro-attenuating norketamine (NANKET) compound, including norketamine,any compound of Formula I, (I-A), (I-B) and any of the compoundsdescribed in Tables A-D, as described herein, e.g., an oralmodified-release, single layer, tablet composition, such that (1) thesubject is effectively treated without causing neurologically toxicspikes in ketamine and/or norketamine plasma concentrations in thesubject following an oral administration event, and/or (2) a disease,disorder and/or condition, such as those for which ketamine treatmentmay be considered, tried, indicated or recommended, such as pain,depression, anxiety, traumatic brain injury, stroke, migraines,epilepsy, schizophrenia, asthma, post traumatic disorder, bipolardisorder, alcohol dependence, Alzheimer disease, suicidality, autism,diabetic neuropathy, tinnitus, levodopa-induced dyskinesia, speudobulbareffect, Bulbar function and the like, are effectively treated, preventedand/or managed, without causing neurologically toxic spikes in ketamineand/or norketamine plasma concentrations in the subject following anoral administration event.

In view of the above, it should now be readily apparent to those ofskill in the ketamine art that the present invention offers significantadvantage over current ketamine treatment by affording prescribingpractitioners a safe and effective alternative to current ketaminetherapy that can mimic ketamine infusion therapy and provide atherapeutic benefit in the treatment, prevention and/or management of adisease, disorder and/or condition for which ketamine treatment may beconsidered, tried, indicated or recommended, including but not limitedto the treatment, prevention and/or management of any disease, disorderor condition that concerns, for example, such as pain, depression,anxiety, traumatic brain injury, stroke, migraines, epilepsy,schizophrenia, asthma, post traumatic disorder, bipolar disorder,alcohol dependence, Alzheimer disease, suicidality, autism, diabeticneuropathy, tinnitus, levodopa-induced dyskinesia, speudobulbar effect,Bulbar function and the like.

Quite surprisingly, the novel oral, modified-release NAKET and/or NANKETpharmaceutical formulations and methods of the present inventionaccomplish this important and needed therapeutic objective bystrategically achieving and maintaining therapeutically effectiveketamine and/or norketamine plasma concentrations, e.g., no more thanabout a 10-300 ng/ml ketamine plasma concentration, throughout the drugrelease period from the oral, modified-release NAKET and/or NANKETpharmaceutical formulations following the oral administrative events toeffectively treat, prevent and/or manage a disease, disorder and/orcondition, without causing neurological toxic spikes in ketamine and/ornorketamine plasma concentrations.

IV. BRIEF DESCRIPTION OF FIGURES

The foregoing and other objects, advantages and features of the presentinvention, and the manner in which the same are accomplished, willbecome more readily apparent upon consideration of the followingdetailed description of the invention taken in conjunction with theaccompanying figures and examples, which illustrate embodiments of thepresent invention, wherein:

FIG. 1 is a graphical depiction of the release profile of ketamine froman HPMC matrix, with and without polyacrylic acid (compositions KTM-1through KTM-3);

FIG. 2 is a graphical depiction of the release profile of ketamine fromthe Kollidon matrix, with and without lactose (compositions KTM-4 andKTM-11);

FIG. 3 is a graphical depiction of the release profile of ketamine froma lipid matrix, with and without polyacrylic acid (compositions KTM-9and KTM-12);

FIG. 4 is a graphical depiction of the release profile of ketamine froma PEO matrix of two different molecular weights;

FIG. 5 is a graphical depiction of the ketamine concentration vs. timein the blood of beagle dogs after administration of tablet KTM-2;

FIG. 6 relates to a rat liver homogenate metabolic assay comparing thehalf-life of norketamine and deuterated norketamine compounds 11 and 12;and

FIG. 7 relates to pharmacokinetic (PK) data in rats of norketamine and abis-deuterated norketamine compound 11.

V. DETAILED DESCRIPTION OF THE INVENTION

The market for ketamine for the treatment of conditions such as pain ordepression, or use in migraine (e.g., with aura), refractory asthma,alcohol dependence, epilepsy, brain injury and/or stroke, has beenlargely focused on injections or infusion administration mainly due tothe consequences of exceeding certain plasma concentrations, beyondwhich serious neurological side effects result. Tablet or capsuleformulations of ketamine have generally failed commercially due to therelatively short therapeutic window of orally administered ketamine,which requires an oral administration of multiple daily doses of thedrug; and the increased likelihood of exceeding psychotomimetic toxicplasma concentrations of ketamine. And although sustained releaseformulations have been generally considered for essentially all drugs,it is the implementation of this formulation that takes inventivecontribution, and has yet to be achieved for ketamine. Such evidencecould not be clearer than from the large commercial need that remains inthe market.

In this regard, current professionals are eager for alternatives toketamine intravenous infusion for 24-hour therapeutically effectiveplasma concentration profile, while seeking to utilize the long-studiedand predictable nature of ketamine as a therapeutic. However, evenintricate, stratified tablets of other NMDA receptor antagonists such asdextromethorphan or amantadine that offer delayed release of a corematerial subsequent to the release of a separately formulated outerlayer have not been able to achieve the release of an NMDA receptorantagonist for periods greater than 12 hours.

As confirmation, several common matrixes of the inactive pharmaceuticalingredients known in the art for the efficient controlled release weretested, and were unable to achieve 24 hour release profile. Using acontrolled release matrix comprised of the hydroxypropyl methylcelluloseand starch, a complete release of ketamine was observed in about 12hours. Further, in the lipid-based matrices containing as much as 20% ofCompritol ATO 888 (Glycerol behenate, Gattesfosse), ketamine could notbe retained for more than 4-6 hours.

However, in order to maintain a therapeutically effective drugconcentration in a once-a-day application analogous to the ketamineinfusion, but which is more convenient for the patient care, ketamineand/or norketamine release should approach 12 to 24 hours, and in amanner that does not afford spikes in ketamine and/or norketamine plasmaconcentration. As such, the present invention provides oral,modified-release neuro-attenuating ketamine (NAKET) formulations and/ororal, modified-release neuro-attenuating norketamine (NANKET)formulations, methods of treatment, and methods of administration, whichensure the steady release of a therapeutically effective concentrationof ketamine and/or norketamine from an oral modified-releasepharmaceutical composition, without causing sedative or psychotomimetictoxic spikes in ketamine and/or norketamine plasma concentration.

In particular, the present invention provides an oral, modified-releaseformulation of aNAKET compound, including ketamine, e.g., a single layertablet formulation. In certain specific embodiments, the oral,modified-release NAKET formulations, and methods of administration,provide steady administration of NAKET to a subject for 12 hours orgreater, for example, 24 hours or greater, for example, up to 36 hours,after a single administration event, e.g., oral administration of adesignated amount of the formulation, whether in one pill, or multiplepills.

In another particular aspect, the present invention provides an oral,modified-release formulation of a NANKET compound, includingnorketamine, e.g., a single layer tablet formulation. In certainspecific embodiments, the oral, modified-release NANKET formulations,and methods of administration, provide steady administration of NANKETto a subject for 12 hours or greater, for example, 24 hours or greater,for example, up to 36 hours, after a single administration event, e.g.,oral administration of a designated amount of the modified-releaseformulation, whether in one pill, or multiple pills. In certainembodiments, however, reduction of this therapeutic window may bedesirable in order to achieve certain advantages for these NAKET and/orNANKET modified-release formulations, such as tamper resistance.

The present invention, including compounds, methods, and pharmaceuticalcompositions/formulations will be described with reference to thefollowing definitions which, for convenience, are set forth below.Unless otherwise specified, the below terms used herein are defined asfollows:

I. Definitions

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

The language “and/or” is used herein as a shorthand notation torepresent the expression “and,” describing the combination of items, aswell as “or,” describing the items in the alternative form. For example,“ketamine and/or norketamine” is shorthand notation for the following:(1) ketamine and norketamine (i.e., both), and (2) ketamine ornorketamine (i.e., either one).

The term “compound” when referring to a compound of this invention,refers to a collection or population of molecules having an identicalchemical structure, except that there may be isotopic variation amongthe constituent atoms of the molecules. Thus, it will be clear to thoseof skill in the art that a compound represented by a particular chemicalstructure containing indicated deuterium atoms, will also contain lesseramounts of isotopologues having hydrogen atoms at one or more of thedesignated deuterium positions in that structure. The relative amount ofsuch isotopologues in a compound of this invention will depend upon anumber of factors including the isotopic purity of deuterated reagentsused to make the compound and the efficiency of incorporation ofdeuterium in the various synthesis steps used to prepare the compound.However, as set forth above the relative amount of such isotopologues intoto will preferably be less than about 49.9% of the compound. In otherembodiments, the relative amount of such isotopologues in toto will beless than about 47.5%, less than about 40%, less than about 32.5%, lessthan about 25%, less than about 17.5%, less than about 10%, less thanabout 5%, less than about 3%, less than about 1%, or less than about0.5% of the compound.

As used herein, “isotopically enriched” refers to a compound that hasbeen enriched synthetically with one or more heavy atom isotopes (e.g.deuterium). Because isotopic enrichment is not 100% effective, there canbe impurities of the compound that are of lesser states of enrichmentand these will have a lower mass. Likewise, because of over-enrichment(undesired enrichment) and because of natural isotopic abundance, therecan be impurities of greater mass.

Certain compounds of the present invention possess asymmetric carbonatoms (optical or chiral centers) or double bonds; the enantiomers,racemates, diastereomers, tautomers, geometric isomers, stereoisometricforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)-isomers, and individual isomers are encompassed within the scopeof the present invention. The compounds of the present invention do notinclude those that are known in art to be too unstable to synthesizeand/or isolate. The present invention is meant to include compounds inracemic and optically pure forms. Optically active (R)- and (S)-isomersmay be prepared using chiral synthons or chiral reagents, or resolvedusing conventional techniques. When the compounds described hereincontain olefinic bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.

The term “about”, as used herein, means an acceptable margin of errorfor a particular value, which depends in part on how the value ismeasured or determined. In certain embodiments, “about” as used hereinwill be understood by persons of ordinary skill in the art to mean up toplus or minus 20% of the particular term. In further embodiments,“about” as used herein will be understood by persons of ordinary skillin the art to mean up to plus or minus 10% of the particular term.

The term “isolated” as used herein, means having been removed from or isfree of other compounds or biological and/or chemical materials presentwhen the compound is first formed. The term “isolated” embracescompounds isolated from natural sources as well aschemically-synthesized compounds.

As used herein, the term “substantially pure” means sufficientlyhomogeneous to appear free of readily detectable impurities asdetermined by standard analytical methods, such as thin layerchromatography (TLC), gel electrophoresis, high performance liquidchromatography (HPLC), nuclear magnetic resonance (NMR), and massspectrometry (MS); or sufficiently pure such that further purificationwould not detectably alter the physical and chemical properties, orbiological and pharmacological properties, such as enzymatic andbiological activities, of the substance. In certain embodiments,“substantially pure” refers to a collection of molecules, wherein atleast about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,about 85%, about 90%, about 95%, about 97%, about 98%, about 98.5%,about 99%, about 99.5% or about 99.9% or greater of the molecules are asingle compound, including a racemic mixture or a single stereoisomerthereof, as determined by standard analytical methods.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and thelike. Also included are salts of amino acids such as arginate and thelike, and salts of organic acids like glucuronic or galactunoric acidsand the like (see, for example, Berge et al., “Pharmaceutical Salts”,Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

Thus, the compounds of the present invention may exist as salts, such aswith pharmaceutically acceptable acids. The present invention includessuch salts. Non-limiting examples of such salts include hydrochlorides,hydrobromides, phosphates, sulfates, methanesulfonates, nitrates,maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g.,(+)-tartrates, (−)-tartrates, or mixtures thereof including racemicmixtures), succinates, benzoates, and salts with amino acids such asglutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyliodide, and the like). These salts may be prepared by methods known tothose skilled in the art.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compound maydiffer from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Prodrugs of the compounds described herein may be convertedin vivo after administration. Additionally, prodrugs can be converted tothe compounds of the present invention by chemical or biochemicalmethods in an ex vivo environment, such as, for example, when contactedwith a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, salt solutions (such as Ringer's solution), alcohols, oils,gelatins, carbohydrates such as lactose, amylose or starch, fatty acidesters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, andthe like. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the invention. One of skill inthe art will recognize that other pharmaceutical excipients are usefulin the present invention.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.chemical compounds including biomolecules or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated; however, the resulting reaction product can be produceddirectly from a reaction between the added reagents or from anintermediate from one or more of the added reagents that can be producedin the reaction mixture.

The term “contacting” may include allowing two species to react,interact, or physically touch, wherein the two species may be a compoundas described herein and a protein or enzyme. In some embodimentscontacting includes allowing a compound described herein to interactwith a protein or enzyme that is involved in a signaling pathway.

As defined herein, the term “activation”, “activate”, “activating” andthe like in reference to a protein refers to conversion of a proteininto a biologically active derivative from an initial inactive ordeactivated state. The terms reference activation, or activating,sensitizing, or up-regulating signal transduction or enzymatic activityor the amount of a protein decreased in a disease.

As defined herein, the term “inhibition”, “inhibit”, “inhibiting” andthe like in reference to a protein-inhibitor interaction meansnegatively affecting (e.g. decreasing) the activity or function of theprotein relative to the activity or function of the protein in theabsence of the inhibitor. In embodiments inhibition means negativelyaffecting (e.g. decreasing) the concentration or levels of the proteinrelative to the concentration or level of the protein in the absence ofthe inhibitor. In embodiments, inhibition refers to reduction of adisease or symptoms of disease. In embodiments, inhibition refers to areduction in the activity of a particular protein target. Thus,inhibition includes, at least in part, partially or totally blockingstimulation, decreasing, preventing, or delaying activation, orinactivating, desensitizing, or down-regulating signal transduction orenzymatic activity or the amount of a protein. In embodiments,inhibition refers to a reduction of activity of a target proteinresulting from a direct interaction (e.g. an inhibitor binds to thetarget protein). In embodiments, inhibition refers to a reduction ofactivity of a target protein from an indirect interaction (e.g. aninhibitor binds to a protein that activates the target protein, therebypreventing target protein activation).

The term “ketamine,” as used alone herein, is art-recognized, and is thecommon name for the molecule: (R,S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone, or

Ketamine is a well-known drug that is very water-soluble (e.g.,solubility of the ketamine hydrochloride in water is about 200 mg/ml),and therefore has a high propensity to be rapidly released from apolymer matrix. The term “ketamine” is intended to include both racemicand enantiomerically enriched, e.g. enantiomerically pure, forms. Incertain embodiments, the ketamine is racemic ketamine. In certainembodiments, the ketamine is enantiomerically enriched in oneenantiomer. In particular embodiments, the ketamine is enriched in the Senantiomer. In particular embodiments, the ketamine is enriched in the Renantiomer.

The term “norketamine,” as used alone herein, is art-recognized, and isthe common name for the molecule: (R,S)-2-(2-chlorophenyl)-2-(amino)cyclohexanone, or

Norketamine is a metabolic product of the demethylation of ketamine, andis considered by many to be active and show clearance similar, butsomewhat slower, to that of ketamine; such activity, however, has beenshown to be significantly reduced (roughly one third) as compared withketamine. The term “norketamine” is intended to include both racemic andenantiomerically enriched, e.g. enantiomerically pure, forms. In certainembodiments, the norketamine is racemic ketamine. In certainembodiments, the norketamine is enantiomerically enriched in oneenantiomer. In particular embodiments, the norketamine is enriched inthe S enantiomer. In particular embodiments, the norketamine is enrichedin the R enantiomer.

As used herein, the language “maximum sustained release” describes therelease window for certain formulations of the present inventionformulated to increase the release period to a maximum value, which isultimately limited by the time the gastrointestinal tract naturallyexcretes all drugs with food.

The language “tamper resistance” is art-recognized to describe aspectsof a drug formulation that make it more difficult to use the formulationto abuse the drug moiety of the formulation through extraction forintravenous use, or crushing for freebase use; and therefore reduce therisk for abuse of the drug.

As used herein, the term “steady” describes the stable or steady-statelevel of a molecule concentration, e.g., ketamine concentration.

As used herein the term “synthetic” or “synthetically” refers to acompound or composition as described herein that is not naturallyoccurring and that is produced artificially, e.g., via chemicalsynthesis. A “synthetic” compound or composition as described hereinwould not include an in vivo-produced compound or metabolite of anadministered compound or agent.

As used herein, the term “composition” is equivalent to the term“formulation.”

As used herein, the language “administration event” describes theadministration of a subject a given dose, in the form of one or morepills within a short window of time, e.g., less than 10 minutes.

As used herein, the language “release period” describes the time windowin which the neuro-attenuating ketamine is released from the matrix toafford plasma concentrations of ketamine and norketamine. The start timeof the release period is defined from the point of oral administrationto a subject, which is considered nearly equivalent to entry into thestomach, and initial dissolution by gastric enzymes and acid.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” refer to the eradication or amelioration of adisease, disorder, or condition, or of one or more symptoms associatedwith the disease, disorder or condition. In certain embodiments, theterms refer to minimizing the advancement or worsening of the disease,disorder, or condition resulting from the administration of aformulation of the invention to a patient with such a disease, disorder,or condition. In some embodiments, the terms refer to the administrationof a formulation provided herein, after the onset of symptoms of theparticular disease, disorder, or condition. The terms “treat,”“treating”, “treatment”, or the like, as used herein covers thetreatment of a disease, disorder, or condition in a subject, e.g., amammal, and includes at least one of: (i) inhibiting the disease,disorder, or condition, i.e., partially or completely halting itsprogression; (ii) relieving the disease, disorder, or condition, i.e.causing regression of symptoms of the disease, disorder, or condition,or ameliorating a symptom of the disease, disorder, or condition; and(iii) reversal or regression of the disease, disorder, or condition,preferably eliminating or curing of the disease, disorder, or condition.In a particular embodiment the terms “treat,” “treating”, “treatment”,or the like, covers the treatment of a disease, disorder, or conditionin a mammal, e.g., a primate, e.g., a human, and includes at least oneof (i), (ii), and (iii) above. As is known in the art, adjustments forage, body weight, general health, sex, diet, time of administration,drug interaction and the severity of the condition may be necessary, andwill be ascertainable with routine experimentation by one of ordinaryskill in the art based on the invention described herein.

As used herein, the terms “subject”, and “patient” are usedinterchangeably. The terms “subject” and “patient” refer to an animal(e.g., a bird such as a chicken, quail or turkey) or a mammal includingnon-primates (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat,cat, dog, and mouse) and primates (e.g., a monkey, chimpanzee and ahuman). In a particular embodiment, the subject is a human.

As used herein, and unless otherwise specified, the terms “prevent,”“preventing” and/or “prevention” refer to the prevention of the onset,recurrence or spread of a disease, disorder, or condition, or of one ormore symptoms thereof. In certain embodiments, the terms refer to theadministration of neuro-attenuating ketamine (NAKET), aneuro-attenuating norketamine (NANKET), or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, to a subject, with or without other additionalactive compounds, prior to the onset of symptoms, particularly topatients at risk of a disease, disorder, or condition provided herein.The terms encompass the inhibition or reduction of a symptom of theparticular disease, disorder, or condition. Subjects with familialhistory of a disease, disorder, or condition, in particular, arecandidates for preventive regimens in certain embodiments. In addition,subjects who have a history of recurring symptoms are also potentialcandidates for the prevention. In this regard, the terms “prevent,”“preventing” and/or “prevention” may be interchangeably used with theterm “prophylactic treatment.” In certain embodiments, the prevention isachieved by administration of a prophylactically effective amount ofneuro-attenuating ketamine (NAKET), a neuro-attenuating norketamine(NANKET), or any of the compounds described herein (e.g., ketamine,norketamine, a compound according to any one of formulas (I), (I-A),(I-B), and (II), or any of the compounds described in Tables A-D, or inany of the Examples provided herein), or a pharmaceutically acceptablesalt thereof, of the invention.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” or an “effective amount” of an active agent, e.g.,neuro-attenuating ketamine (NAKET), neuro-attenuating norketamine(NANKET), or any of the compounds described herein (e.g., a compoundaccording to any one of formulas (I), (I-A), (I-B), and (II), or any ofthe compounds described in Tables A-D, or in any of the Examplesprovided herein), or a pharmaceutically acceptable salt thereof, is anamount sufficient to provide a therapeutic benefit in the treatment ormanagement of a disease, disorder, or condition, or to delay or minimizeone or more symptoms associated with the disease, disorder, orcondition. A therapeutically effective amount of neuro-attenuatingketamine (NAKET) means an amount of neuro-attenuating ketamine (NAKET),alone or in combination with other therapies or compounds (e.g.,NANKET), which provides a therapeutic benefit in the treatment ormanagement of the disease, disorder, or condition. Likewise, atherapeutically effective amount of any of the compounds describedherein (e.g., a compound according to any one of formulas (I), (I-A),(I-B), and (II), or any of the compounds described in Tables A-D, or inany of the Examples provided herein), or a pharmaceutically acceptablesalt thereof, means an amount of any of the compounds described herein(e.g., a compound according to any one of formulas (I), (I-A), (I-B),and (II), or any of the compounds described in Tables A-D, or in any ofthe Examples provided herein) alone or in combination with othertherapies or compounds (e.g., NANKET), which provides a therapeuticbenefit in the treatment or management of the disease, disorder, orcondition. The term “therapeutically effective amount” can encompass anamount that improves overall therapy, reduces or avoids symptoms orcauses of disease, disorder, or condition, or enhances the therapeuticefficacy of another therapeutic agent. The therapeutically effectiveamount for a particular patient in need of such treatment can bedetermined by considering various factors, such as the conditiontreated, the overall health of the patient, method of administration,the severity of side-effects, and the like. For any compound describedherein, the therapeutically effective amount can be initially determinedfrom cell culture assays. Target concentrations will be thoseconcentrations of active compound(s) that are capable of achieving themethods described herein, as measured using the methods described hereinor known in the art. As is well known in the art, therapeuticallyeffective amounts for use in humans can also be determined from animalmodels. For example, a dose for humans can be formulated to achieve aconcentration that has been found to be effective in animals. The dosagein humans can be adjusted by monitoring compounds effectiveness andadjusting the dosage upwards or downwards, as described above. Adjustingthe dose to achieve maximal efficacy in humans based on the methodsdescribed above and other methods is well within the capabilities of theordinarily skilled artisan.

As used herein, and unless otherwise specified, the terms “manage,”“managing” and “management”, are used interchangeably herein and referto preventing or slowing the progression, spread or worsening of adisease, disorder, or condition, or of one or more symptoms thereof.Often, the beneficial effects that a subject derives from a prophylacticand/or therapeutic agent do not result in a cure of the disease,disorder, or condition. In this regard, the terms “manage,” “managing”and/or “management”, encompass treating a subject who had suffered fromthe particular disease, disorder, or condition in an attempt to preventor minimize the recurrence of the disease, disorder, or condition.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of an active agent, e.g., neuro-attenuating ketamine(NAKET), is an amount sufficient to prevent a disease, disorder, orcondition, or prevent its recurrence. A prophylactically effectiveamount of neuro-attenuating ketamine (NAKET) means an amount ofneuro-attenuating ketamine (NAKET), alone or in combination with otheragents (e.g., NANKET), which provides a prophylactic benefit in theprevention of the disease. The term “prophylactically effective amount”can encompass an amount that improves overall prophylaxis or enhancesthe prophylactic efficacy of another prophylactic agent. Likewise, aprophylactically effective amount of any of the compounds describedherein (e.g., a compound according to any one of formulas (I), (I-A),(I-B), and (II), or any of the compounds described in Tables A-D, or inany of the Examples provided herein), or a pharmaceutically acceptablesalt thereof, means an amount of any of the compounds described herein(e.g., a compound according to any one of formulas (I), (I-A), (I-B),and (II), or any of the compounds described in Tables A-D, or in any ofthe Examples provided herein) alone or in combination with othertherapies or compounds (e.g., NANKET), which provides a prophylacticbenefit in the prevention of the disease.

The language “neurologically toxic spikes” is used herein to describespikes in plasma concentration of ketamine and/or norketamine followingan administration event to a subject that would produce side-effects ofsedation and/or psychotomimetic effects, e.g., hallucination, dizziness,and nausea; which can not only have immediate repercussions, but alsoadversely effect treatment compliance. In particular, ketamine sideeffects may become more pronounced at blood concentration levels above300 ng/L.

“Patient” or “subject” or “subject in need thereof” refers to a livingorganism or animal diagnosed with, suffering from or prone to a disease,disorder or condition that can be treated by administration of anisolated and/or substantially pure, isotopically-enriched,neuro-attenuating norketamine compound, including a pharmaceuticalcomposition formulated therewith, or a novel, oral, modified-releaseNAKET or NANKET pharmaceutical composition as provided herein.Non-limiting examples include humans, other mammals, bovines, rats,mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammaliananimals. In some embodiments, a patient is human.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached. Dosage amounts and intervals can be adjusted individually toprovide levels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

II. Compounds of the Invention

Given the well-known use of ketamine, and the discovery described hereinthat ketamine may be orally formulated to provide oral,modified-release, neuro-attenuating ketamine (NAKET) pharmaceuticalformulations, e.g., with reduced neurological adverse effects ascompared to existing oral formulations, methods and the NAKETformulations of the present invention may comprise ketamine, or certainderivatives thereof. Further based on this collective understanding,relating to ketamine, ketamine derivatives, and formulations thereofdescribed herein to provide NAKET, the present invention also providesfor the use of norketamine for administration alone or in combinationwith other agents (e.g., including NAKET) as neuro-attenuatingnorketamine (NANKET), and considers certain norketamine derivativesadvantageous for administration in these NANKET formulations.

Accordingly, the present invention provides methods and formulations ofthe present invention that may comprise ketamine and/or norketamine, orderivatives thereof, and of any of the compounds described herein (e.g.,a compound according to any one of formulas (I), (I-A), (I-B), and (II),or any of the compounds described in Tables A-D, or in any of theExamples provided herein), or a pharmaceutically acceptable saltthereof. In certain embodiments, the ketamine or norketamine, or any ofthe compounds described herein (e.g., a compound according to any one offormulas (I), (I-A), (I-B), and (II), or any of the compounds describedin Tables A-D, or in any of the Examples provided herein), or apharmaceutically acceptable salt thereof, may be derivatized in anymanner that does not significantly effect formulation as describedherein, or the ability of the ketamine/norketamine to achieve thedesired therapeutic effects described herein, i.e., with similar steadyrelease of a therapeutically effective concentration (e.g., based onindication) of the ketamine/norketamine derivative from an oral,modified-release pharmaceutical formulation without causing sedative orpsychotomimetic toxic spikes in the ketamine or norketamine derivativeplasma concentration.

In certain embodiments of the present invention, the ketamine,norketamine, or derivative thereof, or any of the compounds describedherein (e.g., a compound according to any one of formulas (I), (I-A),(I-B), and (II), or any of the compounds described in Tables A-D, or inany of the Examples provided herein), or a pharmaceutically acceptablesalt thereof, is enantiomerically enriched, e.g. enantiomerically pure,in one enantiomer. In specific embodiments, the ketamine and/ornorketamine, or any of the compounds described herein (e.g., a compoundaccording to any one of formulas (I), (I-A), (I-B), and (II), or any ofthe compounds described in Tables A-D, or in any of the Examplesprovided herein), or a pharmaceutically acceptable salt thereof, isenriched in the S enantiomer (e.g., the carbon marked by “*” in any offormulas (I), (I-A), and (I-B) has the S-configuration), e.g.,S-norketamine.

A. Deuterated Derivatives

In a particular embodiment of the invention the derivative may be adeuterated derivative. For example, the ketamine or norketamine may bedeuterated with one deuterium atom. In certain embodiments, the ketamineor norketamine may be deuterated with two deuterium atoms. In certainembodiments, the ketamine or norketamine may be deuterated with threedeuterium atoms. In certain embodiments, the ketamine or norketamine maybe deuterated with more than three deuterium atoms.

In the compounds of the present invention any atom not specificallydesignated as a particular isotope, e.g., deuterium, is meant torepresent any stable isotope of that atom unless otherwise stated.Unless otherwise stated, when a position is designated specifically as“H” or “hydrogen”, the position is understood to have hydrogen at itsnatural abundance isotopic composition. It will be recognized that somevariation of natural isotopic abundance occurs in a synthesized compounddepending upon the origin of chemical materials used in the synthesis.Thus, a preparation of a particular compound will inherently containsmall amounts of deuterated and/or ¹³C-containing isotopologues. Theconcentration of such naturally abundant stable hydrogen and carbonisotopes, notwithstanding this variation, is small and immaterial ascompared to the degree of stable isotopic substitution of compounds ofthis invention. See, for instance, Wada E et al, Seikagaku 1994, 66:15;Ganes L Z et al., Comp Biochem Physiol Mol Integr Physiol 1998, 119:725.In a compound of this invention, when a particular position isdesignated as having deuterium, it is understood that the abundance ofdeuterium at that position is substantially greater than the naturalabundance of deuterium, which is about 0.015%. Positions designated ashaving deuterium typically have a minimum isotopic enrichment factor ofat least 3000 (45% deuterium incorporation) at each atom designated asdeuterium in said compound.

The term “isotopic enrichment factor” as used herein means the ratiobetween the isotopic abundance and the natural abundance of a specifiedisotope. In certain embodiments, a compound of this invention has anisotopic enrichment factor for each designated deuterium atom of atleast about 3500 (52.5% deuterium incorporation at each designateddeuterium atom), at least about 4000 (60% deuterium incorporation), atleast 4500 (67.5% deuterium incorporation), at least about 5000 (75%deuterium incorporation), at least 5500 (82.5% deuterium incorporation),at least abiut 6000 (90% deuterium incorporation), at least about 6333.3(95% deuterium incorporation), at least about 6466.7 (97% deuteriumincorporation), at least about 6600 (99% deuterium incorporation), or atleast about 6633.3 (99.5% deuterium incorporation).

In certain embodiments, each atom not specified as deuterium in any ofthe compounds of the instant invention is present at its naturalisotopic abundance.

i. Deuterated Norketamine and Related Compounds

Given the present disclosure and insight, deuterated norketamine isparticularly attractive for clinical applications due to the kineticdeuterium isotope effect, which would lead to decreased metabolicoxidation rates of these species. Such in vivo metabolic transformationsof norketamine are mediated by the CYP enzymes and take place insignificant part on the cyclohexanone part of the molecule bydehydrogenation, hydroxylation and glucuronidation of the hydroxylatedderivatives. However, some metabolites originate from hydrogenation ofthe aryl ring. In general, the deuterium isotope effect, along with theformulations of the present invention offer very advantageous therapiesfor uses in the methods described herein.

In one aspect, the invention features a neuro-attenuating norketamine(NANKET) compound, or a pharmaceutically acceptable salt thereof.

In one aspect, the invention features a purified neuro-attenuatingnorketamine (NANKET) compound, or a pharmaceutically acceptable saltthereof.

In another aspect, the invention features an isotopically-enrichedneuro-attenuating norketamine (NANKET) compound, or a pharmaceuticallyacceptable salt thereof, as described herein.

In one aspect, the invention features a purified, isotopically-enrichedneuro-attenuating norketamine (NANKET) compound, or a pharmaceuticallyacceptable salt thereof, as described herein.

In still another aspect, the invention features a formulation comprisingneuro-attenuating norketamine (NANKET) compound, or a pharmaceuticallyacceptable salt thereof, as described herein.

In another aspect, the invention features a composition comprising aneuro-attenuating norketamine (NANKET) compound, or a pharmaceuticallyacceptable salt thereof, as described herein.

In another aspect, the invention features a pharmaceutically acceptablesalt of a neuro-attenuating norketamine (NANKET) compound, or apharmaceutically acceptable salt thereof, as described herein.

In another aspect, the invention features an isolated neuro-attenuatingnorketamine (NANKET) compound, or a pharmaceutically acceptable saltthereof.

In another aspect, the invention features an istopically-enriched (e.g.,a deuterium-enriched) neuro-attenuating norketamine (NANKET) compound,or a pharmaceutically acceptable salt thereof.

In another aspect, the invention features a synthetic composition ofmatter comprising a neuro-attenuating norketamine (NANKET) compound, ora pharmaceutically acceptable salt thereof.

In another aspect, the invention features a synthetic composition ofmatter comprising an istopically-enriched (e.g., a deuterium-enriched)neuro-attenuating norketamine (NANKET) compound, or a pharmaceuticallyacceptable salt thereof.

In another aspect, the invention features a pharmaceutical compositionfor treating a subject diagnosed with, suffering from, or suspectible toa disease, disorder, or condition (e.g., such as those for whichketamine treatment may be indicated), wherein the subject is in need ofthe treatment, said pharmaceutical composition comprising:

-   -   (a) a neuro-attenuating norketamine (NANKET) compound, or a        pharmaceutically acceptable salt thereof, as described herein;        and    -   (b) a pharmaceutically acceptable excipient.

In still another aspect, the invention features a pharmaceuticalcomposition comprising

-   -   (a) a neuro-attenuating norketamine (NANKET) compound, or a        pharmaceutically acceptable salt thereof, as described herein;        and    -   (b) a pharmaceutically acceptable excipient.

In another aspect, the invention features a method of treating a subjectdiagnosed with, suffering from, or suspectible to a disease, disorder,or condition (e.g., those for which ketamine treatment may beindicated), the method comprising administering to the subjectneuro-attenuating norketamine (NANKET) compound as described herein, ora pharmaceutically acceptable salt thereof, in an effective amount fortreating, preventing, and/or managing the disease, disorder, orcondition.

In one aspect, the invention features a compound of formula (I), or apharmaceutically acceptable salt thereof.

In one aspect, the invention features a purified compound of formula(I), or a pharmaceutically acceptable salt thereof.

In another aspect, the invention features an isotopically-enrichedcompound of formula (I), or a pharmaceutically acceptable salt thereof,as described herein.

In one aspect, the invention features a purified, isotopically-enrichedcompound of formula (I), or a pharmaceutically acceptable salt thereof,as described herein.

In still another aspect, the invention features a formulation comprisinga compound of formula (I), or a pharmaceutically acceptable saltthereof, as described herein.

In another aspect, the invention features a composition comprising acompound of formula (I), or a pharmaceutically acceptable salt thereof,as described herein.

In another aspect, the invention features a pharmaceutically acceptablesalt of a compound of formula (I), or a pharmaceutically acceptable saltthereof, as described herein.

In another aspect, the invention features an isolated compound offormula (I), or a pharmaceutically acceptable salt thereof.

In another aspect, the invention features an istopically-enriched (e.g.,a deuterium-enriched) compound of formula (I), or a pharmaceuticallyacceptable salt thereof.

In another aspect, the invention features a synthetic composition ofmatter comprising a compound of formula (I), or a pharmaceuticallyacceptable salt thereof.

In another aspect, the invention features a synthetic composition ofmatter comprising an istopically-enriched (e.g., a deuterium-enriched)compound of formula (I), or a pharmaceutically acceptable salt thereof.

In another aspect, the invention features a pharmaceutical compositionfor treating a subject diagnosed with, suffering from, or suspectible toa disease, disorder, or condition (e.g., such as those for whichketamine treatment may be indicated), wherein the subject is in need ofthe treatment, said pharmaceutical composition comprising:

-   -   (c) a compound of formula (I), or a pharmaceutically acceptable        salt thereof, as described herein; and    -   (d) a pharmaceutically acceptable excipient.

In still another aspect, the invention features a pharmaceuticalcomposition comprising

-   -   (c) a compound of formula (I), or a pharmaceutically acceptable        salt thereof, as described herein; and    -   (d) a pharmaceutically acceptable excipient.

In another aspect, the invention features a method of treating a subjectdiagnosed with, suffering from, or suspectible to a disease, disorder,or condition (e.g., those for which ketamine treatment may beindicated), the method comprising administering to the subject acompound of formula (I) as described herein, or a pharmaceuticallyacceptable salt thereof, in an effective amount for treating,preventing, and/or managing the disease, disorder, or condition.

In certain embodiments of the invention, the compound of formula (I) hasthe following structure,

or a pharmaceutically acceptable salt thereof,wherein

X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, X₁₁, X₁₂, X₁₃, and X₁₄ are eachindependently selected from the group consisting of hydrogen anddeuterium, and wherein at least one of X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈,X₉, X₁₀, X₁₁, X₁₂, X₁₃, and X₁₄ is deuterium.

In certain embodiments of formula (I), when each of X₁, X₂, X₃, and X₄is deuterium, then at least one of X₅, X₆, X₇, X₈, X₉, X₁₀, X₁₁, X₁₂,X₁₃, and X₁₄ is deuterium.

In certain embodiments of formula (I), at least one of X₅, X₆, X₇, X₈,X₉, X₁₀, X₁₁, and X₁₂ is deuterium.

In certain embodiments of formula (I), X₅, X₆, X₇, X₈, X₉, X₁₀, X₁₁, andX₁₂ are deuterium. In further embodiments, X₁₃, and X₁₄ are deuterium.

In certain embodiments of formula (I), X₅ and X₆ are deuterium, X₇ andX₈ are deuterium, X₉ and X₁₀ are deuterium, and/or X₁₁ and X₁₂ aredeuterium.

In certain embodiments of formula (I), X₅ and X₆ are deuterium. Incertain embodiments of formula (I), X₇ and X₈ are hydrogen, X₉ and X₁₀are hydrogen, and/or X₁₁ and X₁₂ are hydrogen. In further embodiments,each of X₇, X₈, X₉, X₁₀, X₁₁, X₁₂, X₁₃, and X₁₄ is hydrogen.

In certain embodiments of formula (I), X₁, X₂, X₃, X₄, are deuterium.

In certain embodiments of formula (I), X₁, X₂, X₃, X₄, are hydrogen

In certain embodiments of formula (I), X₅, X₆, X₇, X₈ are deuterium.

In certain embodiments of formula (I), X₅, X₆, X₇, and X₈ are hydrogen.

In certain embodiments of formula (I), X₁₃ and X₁₄ are deuterium.

In certain embodiments of formula (I), X₁₃ and X₁₄ are hydrogen.

In certain embodiments, the compound of formula (I) may be isolated.

In certain embodiments, the compound of formula (I) may be purified.

Accordingly, the present invention provides a composition enriched inthe deuterated derivative over the non-deuterated analog.

In certain embodiments, the compound of formula (I) is isolated orpurified, e.g., the compound of formula (I) is present at a purity of atleast 50% by weight (e.g., at least about 55%, about 60%, about 65%,about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about97%, about 98%, about 98.5%, about 99%, about 99.5% or about 99.9% orgreater) of the total amount of isotopologues of formula (I) present.Thus, in particular embodiments, a composition comprising a compound offormula (I) includes a distribution of isotopologues of the compound,provided at least about 50% of the isotopologues by weight are therecited compound. In further embodiments, at least about 90%, about 95%,about 97%, about 98%, about 98.5%, about 99%, about 99.5% or about 99.9%or greater of the isotopologues by weight are the recited compound.

In certain embodiments, any position in the compound of formula (I)designated as being deuterium has a minimum deuterium incorporation ofat least about 45% (e.g., at least about 52.5%, at least about 60%, atleast about 67.5%, at least about 75%, at least about 82.5%, at leastabout 90%, at least about 95%, at least about 97%, at least about 99%,or at least about 99.5%) at the designated position(s) of the compoundof formula (I). Thus, in particular embodiments, a compositioncomprising a compound of formula (I) includes a distribution ofisotopologues of the compound, provided at least about 45% of theisotopologues include a D at the designated position(s). In furtherembodiments, at least about 90%, about 95%, about 97%, about 98%, about98.5%, about 99%, about 99.5% or about 99.9% or greater of theisotopologues include a D at the designated position(s).

In certain embodiments, a compound of formula (I) is “substantially freeof” other isotopologues of the compound. For example, less than about50%, less than about 25%, less than about 10%, less than about 5%, lessthan about 2%, less than about 1%, or less than about 0.5% of otherisotopologues are present.

The term “isotopologue” refers to a species that has the same chemicalstructure and formula as a specific compound of this invention, with theexception of the isotopic composition at one or more positions, e.g., Hvs. D. Thus an isotopologue differs from a specific compound of thisinvention in the isotopic composition thereof.

In one aspect, the invention features a compound of formula (I-A) or(I-B), or a pharmaceutically acceptable salt thereof.

In one aspect, the invention features a purified compound of formula(I-A) or (I-B), or a pharmaceutically acceptable salt thereof.

In another aspect, the invention features an isotopically-enrichedcompound of formula (I-A) or (I-B), or a pharmaceutically acceptablesalt thereof, as described herein.

In one aspect, the invention features a purified, isotopically-enrichedcompound of formula (I-A) or (I-B), or a pharmaceutically acceptablesalt thereof, as described herein.

In still another aspect, the invention features a formulation comprisinga compound of formula (I-A) or (I-B), or a pharmaceutically acceptablesalt thereof, as described herein.

In another aspect, the invention features a composition comprising acompound of formula (I-A) or (I-B), or a pharmaceutically acceptablesalt thereof, as described herein.

In another aspect, the invention a pharmaceutically acceptable salt of acompound of formula (I-A) or (I-B), or a pharmaceutically acceptablesalt thereof, as described herein.

In still another aspect, the invention features a pharmaceuticalcomposition comprising

-   -   (a) a compound of formula (I-A) or (I-B), or a pharmaceutically        acceptable salt thereof, as described herein; and    -   (b) a pharmaceutically acceptable excipient.

In certain embodiments of the invention, the compound of formula (I-A)has the following structure,

or a pharmaceutically acceptable salt thereof,wherein

X₁, X₂, X₃, X₄, X₆, X₇, X₈, X₉, X₁₀, X₁₁, X₁₂, X₁₃, and X₁₄ are eachindependently selected from the group consisting of hydrogen anddeuterium, and wherein at least one of X₁, X₂, X₃, X₄, X₆, X₇, X₈, X₉,X₁₀, X₁₁, X₁₂, X₁₃, and X₁₄ is deuterium.

In certain embodiments of formula (I-A), when each of X₁, X₂, X₃, and X₄is deuterium, then at least one of X₆, X₇, X₈, X₉, X₁₀, X₁₁, X₁₂, X₁₃,and X₁₄ is deuterium.

In certain embodiments of formula (I-A), at least one of X₆, X₇, X₈, X₉,X₁₀, X₁₁, and X₁₂ is deuterium.

In certain embodiments of formula (I-A), X₆, X₇, X₈, X₉, X₁₀, X₁₁, andX₁₂ are deuterium. In further embodiments, X₁₃, and X₁₄ are deuterium.

In certain embodiments of formula (I-A), X₆ is deuterium, X₇ and X₈ aredeuterium, X₉ and X₁₀ are deuterium, and/or X₁₁ and X₁₂ are deuterium.

In certain embodiments of formula (I-A), X₆ is deuterium. In certainembodiments of formula (I), X₇ and X₈ are hydrogen, X₉ and X₁₀ arehydrogen, and/or X₁₁ and X₁₂ are hydrogen. In further embodiments, eachof X₇, X₈, X₉, X₁₀, X₁₁, X₁₂, X₁₃, and X₁₄ is hydrogen.

In certain embodiments of formula (I-A), X₆, X₇, and X₈ are deuterium.

In certain embodiments of formula (I-A), X₆, X₇, and X₈ are hydrogen.

In certain embodiments of the invention, the compound of formula (I-B)has the following structure,

or a pharmaceutically acceptable salt thereof,wherein

X₁, X₂, X₃, X₄, X₆, X₈, X₉, X₁₀, X₁₁, X₁₂, X₁₃, and X₁₄ are eachindependently selected from the group consisting of hydrogen anddeuterium, and wherein at least one of X₁, X₂, X₃, X₄, X₆, X₈, X₉, X₁₀,X₁₁, X₁₂, X₁₃, and X₁₄ is deuterium.

In certain embodiments of formula (I-B), when each of X₁, X₂, X₃, and X₄is deuterium, then at least one of X₆, X₈, X₉, X₁₀, X₁₁, X₁₂, X₁₃, andX₁₄ is deuterium.

In certain embodiments of formula (I-B), at least one of X₆, X₈, X₉,X₁₀, X₁₁, and X₁₂ is deuterium.

In certain embodiments of formula (I-B), X₆, X₈, X₉, X₁₀, X₁₁, and X₁₂are deuterium. In further embodiments, X₁₃, and X₁₄ are deuterium.

In certain embodiments of formula (I-B), X₆ is deuterium, X₈ isdeuterium, X₉ and X₁₀ are deuterium, and/or X₁₁ and X₁₂ are deuterium.

In certain embodiments of formula (I-B), X₆ is deuterium. In certainembodiments of formula (I), X₈ is hydrogen, X₉ and X₁₀ are hydrogen,and/or X₁₁ and X₁₂ are hydrogen. In further embodiments, each of X₈, X₉,X₁₀, X₁₁, X₁₂, X₁₃, and X₁₄ is hydrogen.

In certain embodiments of formula (I-B), X₆ and X₈ are deuterium.

In certain embodiments of formula (I-B), X₆ and X₈ are hydrogen.

In certain embodiments of formula (I-A) and/or (I-B), X₁, X₂, X₃, X₄,are deuterium.

In certain embodiments of formula (I-A) and/or (I-B), X₁, X₂, X₃, X₄,are hydrogen

In certain embodiments of formula (I-A) and/or (I-B), X₁₃ and X₁₄ aredeuterium.

In certain embodiments of formula (I-A) and/or (I-B), X₁₃ and X₁₄ arehydrogen.

In certain embodiments, the compound of formula (I-A) and/or (I-B) maybe isolated.

In certain embodiments, the compound of formula (I-A) and/or (I-B) maybe purified. Accordingly, the present invention provides a compositionenriched in the deuterated derivative over the non-deuterated analog.

In certain embodiments, the compound of formula (I-A) and/or (I-B) isisolated or purified. For example, the compound of formula (I-A) ispresent at a purity of at least about 50% by weight (e.g., at leastabout 55%, about 60%, about 65%, about 70%, about about 75%, about 80%,about 85%, about 90%, about 95%, about 97%, about 98%, about 98.5%,about 99%, about 99.5% or about 99.9% or greater) of the total amount ofisotopologues of formula (I-A) present, or the compound of formula (I-B)is present at a purity of at least about 50% by weight (e.g., at leastabout 55%, about 60%, about 65%, about 70%, about about 75%, about 80%,about 85%, about 90%, about 95%, about 97%, about 98%, about about98.5%, about 99%, about 99.5% or about 99.9% or greater) of the totalamount of isotopologues of formula (I-B) present. Thus, in particularembodiments, a composition comprising a compound of formula (I-A) and/or(I-B) includes a distribution of isotopologues of the compound, providedat least 50% of the isotopologues by weight are the recited compound. Insome embodiments, at least about 90%, about 95%, about 97%, about 98%,about 98.5%, about 99%, about 99.5% or about 99.9% or greater of theisotopologues by weight are the recited compound of formula (I-A). Inother embodiments, at least about 90%, about 95%, about 97%, about 98%,about 98.5%, about 99%, about 99.5% or about 99.9% or greater of theisotopologues by weight are the recited compound of formula (I-B).

In certain embodiments, any position in the compound of formula (I-A)designated as being deuterium has a minimum deuterium incorporation ofat least about 45% (e.g., at least about 52.5%, at least about 60%, atleast about 67.5%, at least about 75%, at least about 82.5%, at leastabout 90%, at least about 95%, at least about 97%, at least about 99%,or at least about 99.5% or greater) at the designated position(s) of thecompound of formula (I-A). Thus, in particular embodiments, acomposition comprising a compound of formula (I-A) includes adistribution of isotopologues of the compound, provided at least about45% of the isotopologues include a D at the designated position(s). Infurther embodiments, at least about 90%, about 95%, about 97%, about98%, about 98.5%, about about 99%, about 99.5% or about 99.9% or greaterof the isotopologues include a D at the designated position(s).

In certain embodiments, any position in the compound of formula (I-B)designated as being deuterium has a minimum deuterium incorporation ofat least about 45% (e.g., at least about 52.5%, at least about 60%, atleast about 67.5%, at least about 75%, at least about about 82.5%, atleast about 90%, at least about 95%, at least about 97%, at least about99%, or at least about 99.5% or greater) at the designated position(s)of the compound of formula (I-B). Thus, in particular embodiments, acomposition comprising a compound of formula (I-B) includes adistribution of isotopologues of the compound, provided at least about45% of the isotopologues include a D at the designated position(s). Infurther embodiments, at least about 90%, about 95%, about 97%, about98%, about 98.5%, about about 99%, about 99.5% or about 99.9% or greaterof the isotopologues include a D at the designated position(s).

In certain embodiments, a compound of formula (I-A) and/or (I-B) is“substantially free of” other isotopologues of the compound. Forexample, less than about 50%, less than about 25%, less than about 10%,less than about 5%, less than about 2%, less than about 1%, or less thanabout 0.5% of other isotopologues are present.

Exemplary compounds according to formula (I), (I-A), and (I-B) areprovided in Tables A-D below.

TABLE A Exemplary Compounds of Formula (I)

11

13

14

15

16

17

18

19

20

21

22

23

24

25

26

TABLE B Exemplary Compounds of Formula (I)

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

TABLE C Exemplary Compounds of Formula (I-A)

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

TABLE D Exemplary Compounds of Formula (I-B)

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

ii. Deuterated Ketamine

In one aspect, the invention features a neuro-attenuating ketamine(NAKET) compound, or a pharmaceutically acceptable salt thereof.

In one aspect, the invention features a purified neuro-attenuatingketamine (NAKET) compound, or a pharmaceutically acceptable saltthereof.

In another aspect, the invention features an isotopically-enrichedneuro-attenuating ketamine (NAKET) compound, or a pharmaceuticallyacceptable salt thereof, as described herein.

In one aspect, the invention features a purified, isotopically-enrichedneuro-attenuating ketamine (NAKET) compound, or a pharmaceuticallyacceptable salt thereof, as described herein.

In still another aspect, the invention features a formulation comprisingneuro-attenuating ketamine (NAKET) compound, or a pharmaceuticallyacceptable salt thereof, as described herein.

In another aspect, the invention features a composition comprising aneuro-attenuating ketamine (NAKET) compound, or a pharmaceuticallyacceptable salt thereof, as described herein.

In another aspect, the invention features a pharmaceutically acceptablesalt of a neuro-attenuating ketamine (NAKET) compound, or apharmaceutically acceptable salt thereof, as described herein.

In another aspect, the invention features an isolated neuro-attenuatingketamine (NAKET) compound, or a pharmaceutically acceptable saltthereof.

In another aspect, the invention features an istopically-enriched (e.g.,a deuterium-enriched) neuro-attenuating ketamine (NAKET) compound, or apharmaceutically acceptable salt thereof.

In another aspect, the invention features a synthetic composition ofmatter comprising a neuro-attenuating ketamine (NAKET) compound, or apharmaceutically acceptable salt thereof.

In another aspect, the invention features a synthetic composition ofmatter comprising an istopically-enriched (e.g., a deuterium-enriched)neuro-attenuating ketamine (NAKET) compound, or a pharmaceuticallyacceptable salt thereof.

In another aspect, the invention features a pharmaceutical compositionfor treating a subject diagnosed with, suffering from, or suspectible toa disease, disorder, or condition (e.g., such as those for whichketamine treatment may be indicated), wherein the subject is in need ofthe treatment, said pharmaceutical composition comprising:

-   -   (a) a neuro-attenuating ketamine (NAKET) compound, or a        pharmaceutically acceptable salt thereof, as described herein;        and    -   (b) a pharmaceutically acceptable excipient.

In still another aspect, the invention features a pharmaceuticalcomposition comprising

-   -   (a) a neuro-attenuating ketamine (NAKET) compound, or a        pharmaceutically acceptable salt thereof, as described herein;        and    -   (b) a pharmaceutically acceptable excipient.

In another aspect, the invention features a method of treating a subjectdiagnosed with, suffering from, or suspectible to a disease, disorder,or condition (e.g., those for which ketamine treatment may beindicated), the method comprising administering to the subjectneuro-attenuating ketamine (NAKET) compound as described herein, or apharmaceutically acceptable salt thereof, in an effective amount fortreating, preventing, and/or managing the disease, disorder, orcondition.

In one aspect, the invention features a compound of formula (II), or apharmaceutically acceptable salt thereof.

In one aspect, the invention features a purified compound of formula(II), or a pharmaceutically acceptable salt thereof.

In another aspect, the invention features an isotopically-enrichedcompound of formula (II), or a pharmaceutically acceptable salt thereof,as described herein.

In one aspect, the invention features a purified, isotopically-enrichedcompound of formula (II), or a pharmaceutically acceptable salt thereof,as described herein.

In still another aspect, the invention features a formulation comprisinga compound of formula (II), or a pharmaceutically acceptable saltthereof, as described herein.

In another aspect, the invention features a composition comprising acompound of formula (II), or a pharmaceutically acceptable salt thereof,as described herein.

In another aspect, the invention a pharmaceutically acceptable salt of acompound of formula (II), or a pharmaceutically acceptable salt thereof,as described herein.

In still another aspect, the invention features a pharmaceuticalcomposition comprising

-   -   (a) a compound of formula formula (II), or a pharmaceutically        acceptable salt thereof, as described herein; and    -   (b) a pharmaceutically acceptable excipient.

In certain embodiments of the invention, the compound of formula (II)has the following structure:

whereinX₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, X₁₁, X₁₂, X₁₃, X₁₄, X₁₅, andX₁₆ are each independently selected from the group consisting ofhydrogen and deuterium, and wherein at least one of X₁, X₂, X₃, X₄, X₅,X₆, X₇, X₈, X₉, X₁₀, X₁₁, X₁₂, X₁₃, X₁₄, X₁₅, and X₁₆ is deuterium.

In certain embodiments of formula (II), X₅, X₆, X₇, X₈, X₉, X₁₀, X₁₁,and X₁₂ are deuterium.

In certain embodiments of formula (II), X₁₄, X₁₅, and X₁₆ are deuterium.In certain embodiments of formula (II), X₁₄, X₁₅, and X₁₆ are hydrogen.

In certain embodiments of formula (II), X₁₃ is hydrogen. In certainembodiments of formula (II), X₁₃ is deuterium.

In certain embodiments of formula (II), X₅, X₆, X₇, X₈, X₉, X₁₀, X₁₁,and X₁₂ are deuterium; and X₁₄, X₁₅, and X₁₆ are deuterium.

In certain embodiments of formula (II), X₅, X₆, X₇, X₈, X₉, X₁₀, X₁₁,and X₁₂ are deuterium; X₁₃ is deuterium; and X₁₄, X₁₅, and X₁₆ aredeuterium.

In certain embodiments of formula (II), X₅ and X₆ are deuterium, X₇ andX₈ are deuterium, X₉ and X₁₀ are deuterium, and/or X₁₁ and X₁₂ aredeuterium.

In certain embodiments of formula (II), X₅ and X₆ are deuterium. Incertain embodiments of formula (II), X₇ and X₈ are hydrogen, X₉ and X₁₀are hydrogen, and/or X₁₁ and X₁₂ are hydrogen. In further embodiments,each of X₇, X₈, X₉, X₁₀, X₁₁, X₁₂, X₁₃, and X₁₄ is hydrogen.

In certain embodiments of formula (II), X₁, X₂, X₃, X₄, are deuterium.

In certain embodiments of formula (II), X₁, X₂, X₃, X₄, are hydrogen

In certain embodiments of formula (II), X₅, X₆, X₇, X₈ are deuterium.

In certain embodiments of formula (II), X₅, X₆, X₇, and X₈ are hydrogen.

In certain embodiments of formula (II), X₁₃ and X₁₄ are deuterium.

In certain embodiments of formula (II), X₁₃ and X₁₄ are hydrogen.

In certain embodiments, the compound of formula (II) may be isolated.

In certain embodiments, the compound of formula (II) may be purified.

Accordingly, the present invention provides a composition enriched inthe deuterated derivative over the non-deuterated analog.

In certain embodiments, the compound of formula (II) is isolated orpurified, e.g., the compound of formula (II) is present at a purity ofat least about 50% by weight (e.g., at least about 55%, about 60%, about65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%,about 97%, about 98%, about 98.5%, about 99%, about 99.5% or about 99.9%or greater) of the total amount of isotopologues of formula (II)present. Thus, in particular embodiments, a composition comprising acompound of formula (II) includes a distribution of isotopologues of thecompound, provided at least about 50% of the isotopologues by weight arethe recited compound. In further embodiments, at least about 90%, about95%, about 97%, about 98%, about 98.5%, about 99%, about 99.5% or about99.9% or greater of the isotopologues by weight are the recitedcompound.

In certain embodiments, any position in the compound of formula (II)designated as having D has a minimum deuterium incorporation of at leastabout 45% (e.g., at least about 52.5%, at least about 60%, at leastabout 67.5%, at least about 75%, at least about 82.5%, at least about90%, at least about 95%, at least about 97%, at least about 99%, or atleast about 99.5% or greater) at the designated position(s) of thecompound of formula (II). Thus, in particular embodiments, a compositioncomprising a compound of formula (II) includes a distribution ofisotopologues of the compound, provided at least about 45% of theisotopologues include a D at the designated position(s). In furtherembodiments, at least about 90%, about 95%, about 97%, about 98%, about98.5%, about 99%, about 99.5% or about 99.9% or greater of theisotopologues include a D at the designated position(s).

In certain embodiments, a compound of formula (II) is “substantiallyfree of” other isotopologues of the compound, e.g., less than about 50%,less than about 25%, less than about 10%, less than about 5%, less thanabout 2%, less than about 1%, or less than about 0.5% of otherisotopologues are present.

II. Formulations of the Invention

In certain embodiments, the invention provides a pharmaceuticalcomposition, e.g., a pharmaceutical composition formulated for oraladministration, such as pills (e.g., tablets, capsules, caplets,troaches, lozenges, caches, gelcaps, caps, pellets, boluses, pastilles,orally disintegrating tablets, sublingual tablets and buccal tablets),formulated for oral administration, e.g., single-layer tabletcomposition, comprising neuro-attenuating ketamine (NAKET), e.g., withreduced neurological adverse effects compared to existing oralformulations or any of the compounds described herein (e.g., ketamine,norketamine, a compound according to any one of formulas (I), (I-A),(I-B), and (II), or any of the compounds described in Tables A-D, or inany of the Examples provided herein), or a pharmaceutically acceptablesalt thereof. For clarity, the “neuro-attenuating ketamine (NAKET)”utilized in the present invention is ketamine, or a ketamine derivativethat is engineered to act in a similar fashion, formulated to ensure thesteady release of a therapeutically effective concentration of ketamineand/or the ketamine derivative from an oral pharmaceutical compositionwithout sedative or psychotomimetic toxic spikes in ketamine and/orketamine derivative plasma concentration. Such spikes in ketamine plasmaconcentration have been well-documented to have serious psychotomimeticdirected side effects including, but not limited to hallucination,dizziness, and nausea; which can not only have immediate repercussions,but also adversely effect treatment compliance. In this regard, thepresent invention provides novel and inventive formulations for oraladministration comprising, e.g., optimal matrices discovered for thelong-term steady release of a neuro-attenuating ketamine (NAKET)compound, including ketamine, with reduced sedative and psychotomimeticside effects.

In certain embodiments, the invention provides a pharmaceuticalcomposition, e.g., a pharmaceutical composition formulated for oraladministration, such as pills (e.g., tablets, capsules, caplets,troaches, lozenges, caches, gelcaps, caps, pellets, boluses, pastilles,orally disintegrating tablets, sublingual tablets and buccal tablets)for oral administration, e.g., single-layer tablet composition,comprising a neuro-attenuating norketamine (NANKET), e.g., with reducedneurological adverse effects compared to existing oral formulations, orany of the compounds described herein (e.g., a compound according to anyone of formulas (I), (I-A), (I-B), and (II), or any of the compoundsdescribed in Tables A-D, or in any of the Examples provided herein), ora pharmaceutically acceptable salt thereof. For clarity, the“neuro-attenuating norketamine (NANKET)” utilized in the presentinvention is norketamine, or a norketamine derivative that is engineeredto act in a similar fashion, formulated to ensure the steady release ofa therapeutically effective concentration of norketamine and/or thenorketamine derivative from an oral pharmaceutical composition withoutsedative or psychotomimetic toxic spikes in norketamine and/ornorketamine derivative plasma concentration.

In certain embodiments, the neuro-attenuating ketamine ispsychotomimetic-attenuating ketamine (PAKET), wherein the neurologicallytoxic spikes are psychotomimetic toxic spikes, including but are notlimited to hallucination, dizziness, and nausea.

In certain embodiments, the neuro-attenuating ketamine ispsychotomimetic-attenuating norketamine (PANKET), wherein theneurologically toxic spikes are psychotomimetic toxic spikes, includingbut are not limited to hallucination, dizziness, and nausea.

In certain embodiments, the pharmaceutical composition (e.g. a tabletcomposition formulated for oral administration such as a single-layertablet composition), comprises any of the compounds described herein(e.g., ketamine, norketamine, a compound according to any one offormulas (I), (I-A), (I-B), and (II), or any of the compounds describedin Tables A-D, or in any of the Examples provided herein), or apharmaceutically acceptable salt thereof.

In certain embodiments of the present invention, the tablet compositionis a modified-release tablet adapted for sustained release andpreferably maximum sustained release.

In certain embodiments of the present invention, the tablet compositionis adapted for tamper resistance. In particular embodiments, the tabletcomposition comprises polyethylene oxide (PEO), e.g., MW about 2,000 toabout 7,000 KDa, in combination with HPMC. In particular embodiments,the tablet composition may further comprise polyethylene glycol (PEG),e.g., PEG 8K. In particular embodiments, the tablet composition mayfurther comprise polymer carrying one or more negatively charged groups,e.g., polyacrylic acid. In specific embodiments, the tablet compositioncomprising PEO is further subjected to heating/annealing, e.g.,extrusion conditions.

In certain embodiments of the present invention, the NAKET comprises acombination of (i) a water-insoluble neutrally charged non-ionic matrix;(ii) a polymer carrying one or more negatively charged groups; and (iii)ketamine or a ketamine derivative.

In certain embodiments of the present invention, the NANKET comprises acombination of (i) a water-insoluble neutrally charged non-ionic matrix;(ii) a polymer carrying one or more negatively charged groups; and (iii)norketamine or a norketamine derivative.

In certain embodiments of the present invention, the pharmaceuticalcomposition comprises a combination of (i) a water-insoluble neutrallycharged non-ionic matrix; (ii) a polymer carrying one or more negativelycharged groups; and (iii) any of the compounds described herein (e.g.,ketamine, norketamine, a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof.

In certain embodiments of the present invention, the polymer carryingone or more negatively charged groups is selected from the groupconsisting of polyacrylic acid, polylactic acid, polyglycolic acid,polymethacrylate carboxylates, cation-exchange resins, clays, zeolites,hyaluronic acid, anionic gums, salts thereof, and mixtures thereof. Inparticular embodiments, the anionic gum is selected from the groupconsisting of naturally occurring materials and semi-syntheticmaterials. In a specific embodiment, the naturally occurring material isselected from the group consisting of alginic acid, pectin, xanthan gum,carrageenan, locust bean gum, gum arabic, gum karaya, guar gum, and gumtragacanth. In another specific embodiment, the semi-synthetic materialis selected from the group consisting of carboxymethyl-chitin andcellulose gum.

Moreover, without wishing to be bound by theory, in certain embodiments,the role of the polymer carrying one or more negatively charged groups,e.g., moieties of acidic nature as in those of the acidic polymersdescribed herein, surprisingly offers significant retention of ketamine,norketamine, or a derivative thereof, or any of the compounds describedherein (e.g., a compound according to any one of formulas (I), (I-A),(I-B), and (II), or any of the compounds described in Tables A-D, or inany of the Examples provided herein), or a pharmaceutically acceptablesalt thereof, in the matrix. In particular embodiments, this negativecharge may be created in situ, for example, based on release of a protondue to pKa and under certain pH conditions or through electrostaticinteraction/creation of negative charge. Further noting that acidicpolymers may be the salts of the corresponding weak acids that will bethe related protonated acids in the stomach; which, and without wishingto be bound by theory, will neutralize the charge and may reduce theinteractions of the ketamine, norketamine, or derivatives thereof, orany of the compounds described herein (e.g., a compound according to anyone of formulas (I), (I-A), (I-B), and (II), or any of the compoundsdescribed in Tables A-D, or in any of the Examples provided herein), ora pharmaceutically acceptable salt thereof, with the matrix. Inaddition, the release matrix may be further complemented by otherinactive pharmaceutical ingredients to aid in preparation of theappropriate solid dose form such as fillers, disintegrants, flowimproving agents, lubricants, colorants, taste maskers.

In certain embodiments of the present invention, the tablet compositionis adapted for tamper resistance. In particular embodiments, the tabletcomposition comprises polyethylene oxide (PEO), e.g., MW about 2,000 toabout 7,000 KDa. In specific embodiments, the tablet compositioncomprising PEO is further subjected to heating/annealing, e.g.,extrusion.

In certain embodiments of the present invention, the non-ionic matrix isselected from cellulose-based polymers such as HPMC, alone or enhancedby mixing with components selected from the group consisting ofstarches; waxes; neutral gums; polymethacrylates; PVA; PVA/PVP blends;and mixtures thereof.

In certain embodiments of the present invention, the cellulose-basedpolymer is hydroxypropyl methylcellulose (HPMC). In a specificembodiment, the tablet composition comprises about 20-60% hydroxypropylmethylcellulose by weight, about 10-30% starch by weight, or anycombination thereof.

In certain embodiments, the pharmaceutical composition is formulated forrectal or vaginal administration.

In certain embodiments, the pharmaceutical composition is formulated forintranasal or inhalation, like aerosols, inhalers, nebulizers andvaporizers, administration.

In certain embodiments, the pharmaceutical composition is formulated forintraoral administration.

In certain embodiments, the pharmaceutical composition is formulated forparenteral administration, such as intravenous, intramuscular,intradermal, subcutaneous, intraosseous, caudal, intrathecal orintraperitoneal administration.

In certain embodiments, the pharmaceutical composition is formulated foradministration by infusion.

In certain embodiments, the pharmaceutical composition is formulated forsublingual, orally disintegrating or buccal administration.

In certain embodiments, the pharmaceutical composition is formulated forophthalmic or otic administration.

In certain embodiments, the pharmaceutical composition is formulated fortopical administration like pastes, creams, ointments, gels, liquids,sprays, skin patches, dermal patches, balms, salves and implants.

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for, forexample, oral (e.g., intraoral administration or a tablet, caplet,gelcap, cap or capsule composition), rectal, vaginal, intransal,inhalation, otic, ophthalmic, topical, sublingual, orally disintegation,buccal, parenteral, intravenous, subcutaneous or intramuscularadministration, or formulated for administration by infusion, comprisesan amount of ketamine, norketamine, or a derivative thereof, any of thecompounds described herein (e.g., a compound according to any one offormulas (I), (I-A), (I-B), and (II), or any of the compounds describedin Tables A-D, or in any of the Examples provided herein), or apharmaceutically acceptable salt thereof, therapeutically effective forthe treatment of pain. In particular embodiments of the invention, thepain treated is cancer pain, e.g., refractory cancer pain. In particularembodiments of the invention, the pain treated is post-surgical pain. Inparticular embodiments of the invention, the pain treated is orthopedicpain. In particular embodiments of the invention, the pain treated isback pain. In particular embodiments of the invention, the pain treatedis neuropathic pain. In particular embodiments of the invention, thepain treated is dental pain. In particular embodiments of the invention,the pain treated is chronic pain in opioid-tolerant patients.

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for the treatment ofdepression.

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for the treatment ofbrain injury.

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for the treatment ofstroke.

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for use in migraine,e.g., with aura.

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for use in refractoryasthma.

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for use in treatingalcohol dependence.

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for use in treatingpost traumatic stress disorder (PTSD).

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for use in treatingdepression (e.g., treatment resistant depression (TRD) or bipolardepression).

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for use in treatingmajor depressive disorder (MDD).

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for use in treatinganxiety (e.g., generalized anxiety disorder).

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for use in treatingschizophrenia.

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for use in treatingbipolar disorder.

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for use in treatingsuicidality or suicidal ideation.

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for use in treatingautism.

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for use in treatingdiabetic neuropathy.

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for use in treatingneuropathic pain.

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for use in treatingacute pain (e.g., acute trauma pain).

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for use in treatingchronic pain.

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for use in treatinglevodopa-induced dyskinesia.

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for use in treatingor modulating a speudobulbar effect or Bulbar function.

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for use in treatingAlzheimer's disease or conditions associated with Alzheimer's disease(e.g., Alzheimer's dementia or Alzheimer's agitation).

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, therapeutically effective for use in treatingtinnitus.

In certain embodiments of the present invention, the pharmaceuticalcomposition (e.g., a pharmaceutical composition formulated for oral(e.g., intraoral administration or a tablet composition), rectal,intransal, intravenous, sublingual, or intramuscular administration, orformulated for administration by infusion) comprises an amount ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, released from the matrix with a rate of about0.05-2 mg/kg/h over a period of about 12-24 hours, e.g., about 24 hours.

In certain embodiments of the present invention, the neuro-attenuatingketamine achieves a combined concentration of ketamine (or a ketaminederivative) and its metabolite norketamine (or corresponding metabolicnorketamine derivative), or any of the compounds described herein (e.g.,a compound according to any one of formulas (I), (I-A), (I-B), and (II),or any of the compounds described in Tables A-D, or in any of theExamples provided herein), or a pharmaceutically acceptable saltthereof, in plasma in the range of about 10-500 ng/ml, and maintainsthis concentration for duration of the release period. In particularembodiments, the neuro-attenuating ketamine achieves a combinedconcentration of ketamine (or a ketamine derivative) and its metabolitenorketamine (or corresponding metabolic norketamine derivative), or anyof the compounds described herein (e.g., a compound according to any oneof formulas (I), (I-A), (I-B), and (II), or any of the compoundsdescribed in Tables A-D, or in any of the Examples provided herein), ora pharmaceutically acceptable salt thereof, in plasma in the range ofabout 10-300 ng/ml, and maintains this concentration for duration of therelease period. In particular embodiments, the neuro-attenuatingketamine achieves a combined concentration of ketamine (or a ketaminederivative) and its metabolite norketamine (or corresponding metabolicnorketamine derivative) in plasma in the range of about 10-100 ng/ml, orabout 50-100 ng/ml, and maintains this concentration for duration of therelease period. In particular embodiments, the neuro-attenuatingketamine achieves a combined concentration of ketamine (or a ketaminederivative) and its metabolite norketamine (or corresponding metabolicnorketamine derivative) in plasma in the range of about 10-20 ng/ml, andmaintains this concentration for duration of the release period.

In certain embodiments of the present invention, the neuro-attenuatingnorketamine (or a norketamine derivative), or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, achieves a concentration in plasma in the rangeof about 10-500 ng/ml, and maintains this concentration for duration ofthe release period. In particular embodiments, the neuro-attenuatingnorketamine (or a norketamine derivative), or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, achieves a concentration in plasma in the rangeof about 10-300 ng/ml, and maintains this concentration for duration ofthe release period. In particular embodiments, the neuro-attenuatingnorketamine (or a norketamine derivative), or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, achieves a concentration in plasma in the rangeof about 10-100 ng/ml, and maintains this concentration for duration ofthe release period. In particular embodiments, the neuro-attenuatingnorketamine (or a norketamine derivative), or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, achieves a concentration in plasma in the rangeof about 10-20 ng/ml, and maintains this concentration for duration ofthe release period.

In certain embodiments of the present invention, the release period ofthe NAKET or NANKET, or any of the compounds described herein (e.g., acompound according to any one of formulas (I), (I-A), (I-B), and (II),or any of the compounds described in Tables A-D, or in any of theExamples provided herein), or a pharmaceutically acceptable saltthereof, in the formulations of the invention is greater than 4 hours.

In certain embodiments of the present invention, the release period ofthe NAKET or NANKET, or any of the compounds described herein (e.g., acompound according to any one of formulas (I), (I-A), (I-B), and (II),or any of the compounds described in Tables A-D, or in any of theExamples provided herein), or a pharmaceutically acceptable saltthereof, in the formulations of the invention is greater than about 8hours.

In certain embodiments of the present invention, the release period ofthe NAKET or NANKET, or any of the compounds described herein (e.g., acompound according to any one of formulas (I), (I-A), (I-B), and (II),or any of the compounds described in Tables A-D, or in any of theExamples provided herein), or a pharmaceutically acceptable saltthereof, in the formulations of the invention is greater than about 12hours.

In certain embodiments of the present invention, the release period ofthe NAKET or NANKET, or any of the compounds described herein (e.g., acompound according to any one of formulas (I), (I-A), (I-B), and (II),or any of the compounds described in Tables A-D, or in any of theExamples provided herein), or a pharmaceutically acceptable saltthereof, in the formulations of the invention is greater than about 16hours.

In certain embodiments of the present invention, the release period ofthe NAKET or NANKET, or any of the compounds described herein (e.g., acompound according to any one of formulas (I), (I-A), (I-B), and (II),or any of the compounds described in Tables A-D, or in any of theExamples provided herein), or a pharmaceutically acceptable saltthereof, in the formulations of the invention is greater than about 20hours.

In certain embodiments of the present invention, the release period ofthe NAKET or NANKET, or any of the compounds described herein (e.g., acompound according to any one of formulas (I), (I-A), (I-B), and (II),or any of the compounds described in Tables A-D, or in any of theExamples provided herein), or a pharmaceutically acceptable saltthereof, in the formulations of the invention is greater than (or equalto) about 24 hours.

In certain embodiments of the present invention, the release period ofthe NAKET or NANKET, or any of the compounds described herein (e.g., acompound according to any one of formulas (I), (I-A), (I-B), and (II),or any of the compounds described in Tables A-D, or in any of theExamples provided herein), or a pharmaceutically acceptable saltthereof, in the formulations of the invention is greater than (or equalto) about 28 hours.

In certain embodiments of the present invention, the release period ofthe NAKET or NANKET, or any of the compounds described herein (e.g., acompound according to any one of formulas (I), (I-A), (I-B), and (II),or any of the compounds described in Tables A-D, or in any of theExamples provided herein), or a pharmaceutically acceptable saltthereof, in the formulations of the invention is greater than (or equalto) about 32 hours.

In certain embodiments of the present invention, the release period ofthe NAKET or NANKET, or any of the compounds described herein (e.g., acompound according to any one of formulas (I), (I-A), (I-B), and (II),or any of the compounds described in Tables A-D, or in any of theExamples provided herein), or a pharmaceutically acceptable saltthereof, in the formulations of the invention is greater than (or equalto) about 36 hours.

In certain embodiments of the present invention, the release period ofthe NAKET or NANKET, or any of the compounds described herein (e.g., acompound according to any one of formulas (I), (I-A), (I-B), and (II),or any of the compounds described in Tables A-D, or in any of theExamples provided herein), or a pharmaceutically acceptable saltthereof, in the formulations of the invention is less than about 48hours.

In certain embodiments of the present invention, the release period ofthe NAKET or NANKET, or any of the compounds described herein (e.g., acompound according to any one of formulas (I), (I-A), (I-B), and (II),or any of the compounds described in Tables A-D, or in any of theExamples provided herein), or a pharmaceutically acceptable saltthereof, in the formulations of the invention is less than about 36hours.

In certain embodiments of the present invention, the tablet compositionsof the present invention are utilized as a 2-times a day (BID), 3-timesa day (TID) or 4-times a day (QID) application.

In certain embodiments of the present invention, the tablet compositionsof the present invention are utilized as a once a day (QD) application.

In certain embodiments of the present invention, the tablet compositionsof the present invention are utilized as a nightly (QHS) application.

In certain embodiments of the present invention, the tablet compositionsof the present invention are utilized as an as needed (PRN) application.

In certain embodiments of the present invention, the oral pharmaceuticalcompositions are enhanced. In particular embodiments, due to theefficiency of administration, the formulation is able to utilize lessketamine, norketamine, or derivative thereof for treatment to achievethe same effect as comparative oral tablets not described by the presentinvention.

In certain embodiments of the present invention, the oral administrationevent, which provides the appropriate single unit dose, may comprise onesingle pill or multiple pills.

In addition, to protect the tablet from the acidic environment in thestomach and maintain a long-term release, various types of entericcoating may be used in certain embodiments.

In certain embodiments of the present invention, a single-layer tabletor caplet is coated with protective layers of inactive pharmaceuticalingredients to form a modified-release formulation, e.g., to ensuresteady release of the drug from the matrix and avoid concentrationbursts at the early release time points.

Another embodiment of the present invention provides formulation ofketamine, norketamine, or a derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof as a modified-release formulation, that ensuresthe steady release of a therapeutically effective concentration of theketamine, norketamine, or the derivative thereof, or any of thecompounds described herein (e.g., a compound according to any one offormulas (I), (I-A), (I-B), and (II), or any of the compounds describedin Tables A-D, or in any of the Examples provided herein), or apharmaceutically acceptable salt thereof, from such oralmodified-release formulation, without sedative or psychotomimetic toxicspikes in plasma concentration of the ketamine, norketamine, orderivative thereof, or any of the compounds described herein (e.g., acompound according to any one of formulas (I), (I-A), (I-B), and (II),or any of the compounds described in Tables A-D, or in any of theExamples provided herein), or a pharmaceutically acceptable saltthereof. This formulation comprises the ketamine, norketamine, orderivative thereof, or any of the compounds described herein (e.g., acompound according to any one of formulas (I), (I-A), (I-B), and (II),or any of the compounds described in Tables A-D, or in any of theExamples provided herein), or a pharmaceutically acceptable saltthereof, formulated in an osmotic controlled release pharmaceuticalcomposition, such as a tablet, caplet or granules. In these formulationsa single core layer containing the ketamine, norketamine, or derivativethereof, or any of the compounds described herein (e.g., a compoundaccording to any one of formulas (I), (I-A), (I-B), and (II), or any ofthe compounds described in Tables A-D, or in any of the Examplesprovided herein), or a pharmaceutically acceptable salt thereof, (e.g.,as defined by other tablet formulations described herein) is surroundedby semi-permeable membrane with or without drug delivery orifice.Without wishing to be bound by theory, because these systems use waterosmotic pressure for the controlled delivery of the active material,delivery rates are expected to be independent of gastrointestinalconditions. In combination with the novel and inventive aspects of thepresent invention, osmotic asymmetric-membrane technology or AMT (e.g.,technology directed to a single-layer tablet, caplet or granules coatedwith an insoluble, asymmetric microporous membrane produced bycontrolled phase separation) may be used to produce formulations usefulin the methods of treatment and kits described herein.

In certain embodiments of the invention, the ketamine, norketamine, or aderivative thereof, or any of the compounds described herein (e.g., acompound according to any one of formulas (I), (I-A), (I-B), and (II),or any of the compounds described in Tables A-D, or in any of theExamples provided herein), or a pharmaceutically acceptable saltthereof, may be formulated as a pharmaceutically acceptable saltthereof, e.g., ketamine hydrochloride, ketamine aspartate, ketaminesuccinate, etc, such that the ketamine/norketamine counterion does notsignificantly effect formulation as described herein for ketamine,norketamine, or the derivative thereof, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, or the ability of the ketamine, norketamine, orthe derivative thereof, or any of the compounds described herein (e.g.,a compound according to any one of formulas (I), (I-A), (I-B), and (II),or any of the compounds described in Tables A-D, or in any of theExamples provided herein), or a pharmaceutically acceptable saltthereof, to achieve the desired therapeutic effects described herein,i.e., with similar steady release of a therapeutically effectiveconcentration (e.g., based on indication) from an oral pharmaceuticalcomposition, such as a tablet, a caplet, a capsule, a gelcap, a cap orgranules, without sedative or psychotomimetic toxic spikes in theconcentration of ketamine, norketamine, or derivative thereof, or any ofthe compounds described herein (e.g., a compound according to any one offormulas (I), (I-A), (I-B), and (II), or any of the compounds describedin Tables A-D, or in any of the Examples provided herein), or apharmaceutically acceptable salt thereof. Exemplary salts, within thisscope, may include but are not limited to: salts with an inorganic acidsuch as hydrochloric acid, hydrobromic acid, hydriodic acid, nitricacid, perchloric acid, sulfuric acid or phosphoric acid; and salts withan organic acid, such as methanesulfonic acid, trifluoromethanesulfonicacid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,fumaric acid, oxalic acid, maleic acid, citric acid, succinic acid,tartaric acid; and other mineral and carboxylic acids well known tothose skilled in the art. Additional examples may include salts withinorganic cations such as sodium, potassium, calcium, magnesium,lithium, aluminum, zinc, etc; and salts formed with pharmaceuticallyacceptable amines such as ammonia, alkylamines, hydroxyalkylamines,lysine, arginine, N-methylglucamine, procaine and the like. In specificembodiments, the pharmaceutically acceptable salt is a hydrochloridesalt.

Another embodiment of the present invention provides a kit for thetreatment of a subject with ketamine, norketamine, or a derivativethereof, or any of the compounds described herein (e.g., a compoundaccording to any one of formulas (I), (I-A), (I-B), and (II), or any ofthe compounds described in Tables A-D, or in any of the Examplesprovided herein), or a pharmaceutically acceptable salt thereof,comprising pharmaceutical composition, such as an orally administeredpharmaceutical composition like a pill, of any one of the formulationsdescribed herein comprising neuro-attenuating ketamine (NAKET) and/orneuro-attenuating norketamine (NANKET), or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, and instructions for use in the treatment,prevention or management of a disease, disorder or condition, such aspain, e.g., as described herein.

In particular embodiments of the invention, the pain treated is cancerpain, e.g., refractory cancer pain.

In particular embodiments of the invention, the pain treated ispost-surgical pain.

In particular embodiments of the invention, the pain treated isorthopedic pain.

In particular embodiments of the invention, the pain treated is backpain.

In particular embodiments of the invention, the pain treated isneuropathic pain.

In particular embodiments of the invention, the pain treated is dentalpain.

In particular embodiments of the invention, the pain treated is chronicpain in opioid-tolerant patients.

Another embodiment of the present invention provides a kit for thetreatment of a subject with ketamine, norketamine, or a derivativethereof, or any of the compounds described herein (e.g., a compoundaccording to any one of formulas (I), (I-A), (I-B), and (II), or any ofthe compounds described in Tables A-D, or in any of the Examplesprovided herein), or a pharmaceutically acceptable salt thereof,comprising a pharmaceutical composition, such as an orally administeredtablet pharmaceutical composition like a pill, of any one of theformulations of the present invention comprising neuro-attenuatingketamine (NAKET), neuro-attenuating norketamine (NANKET), and/or any ofthe compounds described herein (e.g., a compound according to any one offormulas (I), (I-A), (I-B), and (II), or any of the compounds describedin Tables A-D, or in any of the Examples provided herein), or apharmaceutically acceptable salt thereof, and instructions for use inthe treatment of brain injury.

Another embodiment of the present invention provides a kit for thetreatment of a subject with ketamine, norketamine, or a derivativethereof, or any of the compounds described herein (e.g., a compoundaccording to any one of formulas (I), (I-A), (I-B), and (II), or any ofthe compounds described in Tables A-D, or in any of the Examplesprovided herein), or a pharmaceutically acceptable salt thereof,comprising a pharmaceutical composition, such as an orally administeredtablet pharmaceutical composition like a pill, of any one of theformulations of the present invention comprising neuro-attenuatingketamine (NAKET), neuro-attenuating norketamine (NANKET), and/or any ofthe compounds described herein (e.g., a compound according to any one offormulas (I), (I-A), (I-B), and (II), or any of the compounds describedin Tables A-D, or in any of the Examples provided herein), or apharmaceutically acceptable salt thereof, and instructions for use inthe treatment of depression.

Another embodiment of the present invention provides a kit for thetreatment of a subject with ketamine, norketamine, or a derivativethereof, or any of the compounds described herein (e.g., a compoundaccording to any one of formulas (I), (I-A), (I-B), and (II), or any ofthe compounds described in Tables A-D, or in any of the Examplesprovided herein), or a pharmaceutically acceptable salt thereof,comprising a pharmaceutical composition, such as an orally administeredtablet pharmaceutical composition like a pill, of the formulations ofthe present invention comprising neuro-attenuating ketamine (NAKET),neuro-attenuating norketamine (NANKET), or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, and instructions for use in the treatment ofmigraine, e.g., with aura.

Another embodiment of the present invention provides a kit for thetreatment of a subject with ketamine, norketamine, or a derivativethereof, or any of the compounds described herein (e.g., a compoundaccording to any one of formulas (I), (I-A), (I-B), and (II), or any ofthe compounds described in Tables A-D, or in any of the Examplesprovided herein), or a pharmaceutically acceptable salt thereof,comprising a pharmaceutical composition, such as an orally administeredtablet pharmaceutical composition like a pill, of the present inventioncomprising neuro-attenuating ketamine (NAKET), neuro-attenuatingnorketamine (NANKET), and/or any of the compounds described herein(e.g., a compound according to any one of formulas (I), (I-A), (I-B),and (II), or any of the compounds described in Tables A-D, or in any ofthe Examples provided herein), or a pharmaceutically acceptable saltthereof, and instructions for use in the treatment of refractory asthma.

Another embodiment of the present invention provides a kit for thetreatment of a subject with ketamine, norketamine, or a derivativethereof, or any of the compounds described herein (e.g., a compoundaccording to any one of formulas (I), (I-A), (I-B), and (II), or any ofthe compounds described in Tables A-D, or in any of the Examplesprovided herein), or a pharmaceutically acceptable salt thereof,comprising a pharmaceutical composition, such as an orally administeredtablet pharmaceutical composition like a pill, of any one of theformulations of the present invention comprising neuro-attenuatingketamine (NAKET), neuro-attenuating norketamine (NANKET), or any of thecompounds described herein (e.g., a compound according to any one offormulas (I), (I-A), (I-B), and (II), or any of the compounds describedin Tables A-D, or in any of the Examples provided herein), or apharmaceutically acceptable salt thereof, and instructions for use inthe treatment of stroke.

Another embodiment of the present invention provides a kit for thetreatment of a subject with ketamine, norketamine, or a derivativethereof, or any of the compounds described herein (e.g., a compoundaccording to any one of formulas (I), (I-A), (I-B), and (II), or any ofthe compounds described in Tables A-D, or in any of the Examplesprovided herein), or a pharmaceutically acceptable salt thereof,comprising a pharmaceutical composition, such as an orally administeredtablet pharmaceutical composition like a pill, of any one of theformulations of the present invention comprising neuro-attenuatingketamine (NAKET), neuro-attenuating norketamine (NANKET), and/or any ofthe compounds described herein (e.g., a compound according to any one offormulas (I), (I-A), (I-B), and (II), or any of the compounds describedin Tables A-D, or in any of the Examples provided herein), or apharmaceutically acceptable salt thereof, and instructions for use inthe treatment of alcohol dependence.

In embodiments, the invention features an oral, modified-releasepharmaceutical composition for oral administration to a subject fortreating the subject diagnosed with, suffering from or susceptible to adisease, disorder or condition, such as those for which ketaminetreatment may be indicated, considered or recommeded, wherein thesubject is in need of treatment with said oral, modified-releasepharmaceutical composition, said oral, modified-release pharmaceuticalcomposition comprising:

(a) a drug selected from a group consisting of ketamine, adeuterium-enriched neuro-attenuating ketamine (NAKET) compound,norketamine, and/or a deuterium-enriched neuro-attenuating norketamine(NANKET) compound or a pharmaceutically acceptable salt thereof in aneffective amount for treating, preventing and/or managing the disease,disorder, or condition in the subject; and

(b) a pharmaceutically acceptable excipient;

whereby, upon oral administration of the modified-release pharmaceuticalcomposition to the subject, a steady release of said drug from themodified-release pharmaceutical composition is maintained so that noneurologically toxic spike in the subject's plasma occurs during therelease period of said drug from said pharmaceutical composition.

In certain embodiments of the kit, the instructions for use form anintegrated component of the packaging for the pharmaceuticalcomposition.

A. General Tablet Formulations of the Invention The formulations of theinvention comprise orally administered pharmaceutical compositions, suchas tablet, capsule, caplets, gelcap and cap compositions, which mayinclude uncoated tablets or coated tablets, caplets and caps (includingfilm-coated, sugar-coated tablets, and gastro-resistant/enteric-coatedtablets). The oral pharmaceutical compositions for oral use may includethe active ingredients, e.g., ketamine and/or norketamine, or any of thecompounds described herein (e.g., a compound according to any one offormulas (I), (I-A), (I-B), and (II), or any of the compounds describedin Tables A-D, or in any of the Examples provided herein), or apharmaceutically acceptable salt thereof, mixed with pharmaceuticallyacceptable inactive excipients such as diluents, disintegrating agents,binding agents, lubricating agents, powder flow improving agent, wettingagents, sweetening agents, flavoring agents, coloring agents andpreservatives. Moreover, oral pharmaceutical compositions of the presentinvention are solid dosage forms intended for oral administration, e.g.,obtained by dry granulation with single or multiple compressions ofpowders or granules. In certain embodiments, the oral pharmaceuticalcompositions may be obtained by using wet granulation techniques. Incertain embodiments, the oral pharmaceutical compositions may beobtained by molding, heating/annealing, or extrusion techniques.

In certain embodiments, the oral tablets are right circular solidcylinders, the end surfaces of which are flat or convex, and the edgesof which may be beveled. In particular embodiments, the surfaces areconvex. In addition, they may have lines or break-marks (scoring),symbols or other markings.

In certain embodiments, the break-mark(s) is/are intended to permitaccurate subdivision of the tablet in order to provide doses of lessthan one tablet. In certain embodiments of the invention, the tabletcompositions comprise one or more excipients such as diluents, binders,disintegrating agents, glidants, lubricants, substances capable ofmodifying the behavior of the dosage forms and the active ingredient(s)in the gastrointestinal tract, coloring matter authorized by theappropriate national or regional authority and flavoring substances.When such excipients are used it is necessary to ensure that they do notadversely affect the stability, dissolution rate, bioavailability,safety or efficacy of the active ingredient(s); there must be noincompatibility between any of the components of the dosage form.

Coated tablets are tablets covered with one or more layers of mixturesof substances such as natural or synthetic resins, polymers, gums,fillers, sugars, plasticizers, polyols, waxes, coloring mattersauthorized by the appropriate national or regional authority, andflavoring substances. Such coating materials do not contain any activeingredient, e.g., ketamine, norketamine, or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof. The tablets may be coated for a variety ofreasons such as protection of the active ingredients from burst releasefrom the matrix, air, moisture or light, masking of unpleasant tastesand odors or improvement of appearance. The substance used for coatingmay be applied as a solution or suspension.

In certain embodiments, the manufacturing processes for the oralpharmaceutical compositions, e.g., tablets, meet the requirements ofgood manufacturing practices (GMP). In certain embodiments, one or moremeasures are taken in the manufacture of oral pharmaceuticalcompositions selected from the following: ensure that mixing withexcipients is carried out in a manner that ensures homogeneity; ensurethat the oral pharmaceutical compositions possess a suitable mechanicalstrength to avoid crumbling or breaking on subsequent processing, e.g.,coating, storage and distribution; minimize the degradation of theactive ingredient; minimize the risk of microbial contamination;minimize the risk of cross-contamination. In addition, in themanufacture of scored tablets (tablets bearing a break-mark or marks)for which subdivision is intended in order to provide doses of less thanone tablet measures are taken to: ensure the effectiveness ofbreak-marks with respect to the uniformity of mass or content, asappropriate, of the subdivided parts so that the patient receives theintended dose.

In general a suitable dose will be in the range of about 0.01 to about10 mg per kilogram body weight of the recipient per day, preferably inthe range of about 0.1 to about 5 mg per kilogram body weight per day.Additional details on techniques for formulation and administration arewell described in the scientific and patent literature, see, e.g., thelatest edition of Remington's Pharmaceutical Sciences, Maack PublishingCo, Easton Pa. (“Remington's”). After a pharmaceutical composition hasbeen formulated in an acceptable carrier, it can be placed in anappropriate container and labeled for treatment of an indicatedcondition). For administration of the NAKET or NANKET formulations, orformulations comprising any of the compounds described herein (e.g., acompound according to any one of formulas (I), (I-A), (I-B), and (II),or any of the compounds described in Tables A-D, or in any of theExamples provided herein), or a pharmaceutically acceptable saltthereof, such labeling would include, e.g., instructions concerning theamount, frequency, method of administration, treatment regimen andindications.

B. Compliance with Monographs

In certain embodiments, the formulations of the present inventionconform to certain industry accepted monographs to afford compliancewith the Federal Food Drug and Cosmetic Act. In particular, theformulations of the present invention conform and are consideredacceptable under visual inspection, uniformity of mass analysis,uniformity of content analysis, and/or dissolution/disintegrationanalysis all of which are established by a relevant monograph.

In certain embodiments, throughout manufacturing certain procedures arevalidated and monitored by carrying out appropriate in-process controls.These are designed to guarantee the effectiveness of each stage ofproduction. In-process controls during tablet production may include themoisture content of the final lubricated blend, the size of granules,the flow of the final mixture and, where relevant, the uniformity ofmass of tablet cores before coating. In-process controls during tabletproduction may also include the dimensions (thickness, diameter),uniformity of mass, hardness and/or crushing force, friability,disintegration or dissolution rate (for example, for modified-releasetablets) of the finished dosage form. Suitable test methods that may beused to demonstrate certain of these attributes are known in the art.

In certain embodiments, packaging maybe or is required to be adequate toprotect the pharmaceutical compositions, including tablets, from light,moisture and damage during transportation.

In additional embodiments, the commercially available formulation (e.g.,kit) complies with the labeling requirements established under GoodManufacturing Practices (GMP). Such label includes:

-   -   (1) the name of the pharmaceutical product;    -   (2) the name(s) of the active ingredient(s); International        Nonproprietary Names (INN) should be used wherever possible;    -   (3) the amount of the active ingredient(s) in each tablet and        the number of tablets in the container;    -   (4) the batch (lot) number assigned by the manufacturer;    -   (5) the expiry date and, when required, the date of manufacture;    -   (6) any special storage conditions or handling precautions that        may be necessary;    -   (7) directions for use, warnings, and precautions that may be        necessary;    -   (8) the name and address of the manufacturer or the person        responsible for placing the product on the market;    -   (9) for scored tablets where the directions for use include        subdivision to provide doses of less than one tablet, the label        should also include:—the storage conditions for and the period        of use of those subdivided part(s) not immediately taken or        administered.

In certain embodiments, the pharmaceutical compositions, e.g., tablets,are able to withstand handling, including packaging and transportation,without losing their integrity.

IV. Methods of the Invention

The formulations of the invention may be used in the methods of theinvention, e.g., methods of treatment of the invention. As such, theinvention relates to the method of use of formulations or compositions(e.g., pharmaceutical compositions) of the invention, which containneuro-attenuating ketamine (NAKET), neuro-attenuating norketamine(NANKET), and/or any of the compounds described herein (e.g., a compoundaccording to any one of formulas (I), (I-A), (I-B), and (II), or any ofthe compounds described in Tables A-D, or in any of the Examplesprovided herein), or a pharmaceutically acceptable salt thereof, e.g.,for the treatment of pain. As such, in certain embodiments, theinvention provides for the management of different kinds of pain,including but not limited to refractory cancer pain, neurologic pain,postoperative pain, complex regional pain syndrome (CRPS), migraine,e.g., with aura, and other conditions including depression, alcoholdependence, refractory asthma, epilepsy, acute brain injury and stroke,Alzheimer's disease and other disorders comprising an oraladministration of the formulations of the present invention, describedherein. In certain embodiments, the use of formulations of the presentinvention may be used as a standalone therapy. In certain embodiments,the use of formulations of the present invention may be used as anadjuvant/combination therapy.

In certain embodiments, the invention provides for the management ofdifferent kinds of pain, including but not limited to cancer pain, e.g.,refractory cancer pain; neuropathic pain; opioid-induced hyperalgesiaand opioid-related tolerance; neurologic pain;postoperative/post-surgical pain; complex regional pain syndrome (CRPS);shock; limb amputation; severe chemical or thermal burn injury; sprains,ligament tears, fractures, wounds and other tissue injuries; dentalsurgery, procedures and maladies; labor and delivery; during physicaltherapy; radiation poisoning; acquired immunodeficiency syndrome (AIDS);epidural (or peridural) fibrosis; orthopedic pain; back pain; failedback surgery and failed laminectomy; sciatica; painful sickle cellcrisis; arthritis; autoimmune disease; intractable bladder pain; painassociated with certain viruses, e.g., shingles pain or herpes pain;acute nausea, e.g., pain that may be causing the nausea or the abdominalpain that frequently accompanies sever nausea; migraine, e.g., withaura; and other conditions including depression (e.g., acute depressionor chronic depression), depression along with pain, alcohol dependence,acute agitation, refractory asthma, acute asthma (e.g., unrelated painconditions can induce asthma), epilepsy, acute brain injury and stroke,Alzheimer's disease and other disorders. In addition, the presentinvention includes the treatment/management of any combination of thesetypes of pain or conditions.

In certain embodiments, the pain treated/managed is acute breakthroughpain or pain related to wind-up that can occur in a chronic paincondition.

In particular embodiments of the invention, the pain treated/managed iscancer pain, e.g., refractory cancer pain.

In particular embodiments of the invention, the pain treated/managed ispost-surgical pain.

In particular embodiments of the invention, the pain treated/managed isorthopedic pain.

In particular embodiments of the invention, the pain treated/managed isback pain.

In particular embodiments of the invention, the pain treated/managed isneuropathic pain.

In particular embodiments of the invention, the pain treated/managed isdental pain.

In particular embodiments of the invention, the conditiontreated/managed is depression.

In particular embodiments of the invention, the pain treated/managed ischronic pain in opioid-tolerant patients.

In embodiments, the invention relates to a method of treating a diseaseor condition by modulating NMDA activity, where the method comprisesadministering an effective amount of any of the compounds describedherein (e.g., a compound according to formula (I), or a pharmaceuticallyacceptable salt thereof, or any of the compounds described in TablesA-D, or comprising NAKET or NANKET) to a subject in need thereof. Inembodiments, the disease or condition is selected from: levodopa-induceddyskinesia; dementia (e.g., Alzheimer's dementia), tinnitus, treatmentresistant depression (TRD), major despressive disorder, neuropathicpain, agitation resulting from or associated with Alzheimer's disease,pseudobulbar effect, autism, Bulbar function, generalized anxietydisorder, Alzheimer's disease, schizophrenia, diabetic neuropathy, acutepain, depression, bipolar depression, suicidality, neuropathic pain, orpost-traumatic stress disorder (PTSD). In embodiments, the disease orcondition is a psychiatric or mental disorder (e.g., schizophrenia, mooddisorder, substance induced psychosis, major depressive disorder (MDD),bipolar disorder, bipolar depression (BDep), post-traumatic stressdisorder (PTSD), suicidal ideation, anxiety, obsessive compulsivedisorder (OCD), and treatment-resistant depression (TRD)). In otherembodiments, the disease or condition is a neurological disorder (e.g.,Huntington's disease (HD), Alzheimer's disease (AD), or systemic lupuserythematosus (SLE)).

For example, in one embodiment, the invention provides a method oftreating a subject with ketamine, norketamine, or a derivative thereof,or any of the compounds described herein (e.g., a compound according toany one of formulas (I), (I-A), (I-B), and (II), or any of the compoundsdescribed in Tables A-D, or in any of the Examples provided herein), ora pharmaceutically acceptable salt thereof, comprising the step ofadministering to a subject an orally administered tablet composition,e.g., matrix composition, of the present invention comprisingneuro-attenuating ketamine (NAKET), neuro-attenuating norketamine(NANKET), and/or any of the compounds described herein (e.g., a compoundaccording to any one of formulas (I), (I-A), (I-B), and (II), or any ofthe compounds described in Tables A-D, or in any of the Examplesprovided herein), or a pharmaceutically acceptable salt thereof, suchthat the subject is treated.

The administering physician can provide a method of treatment that isprophylactic or therapeutic by adjusting the amount and timing of NAKET,NANKET, and/or any of the compounds described herein (e.g., a compoundaccording to any one of formulas (I), (I-A), (I-B), and (II), or any ofthe compounds described in Tables A-D, or in any of the Examplesprovided herein), or a pharmaceutically acceptable salt thereof,administration on the basis of observations of one or more symptoms ofthe disorder or condition being treated.

In another embodiment, the invention provides a method of continuousoral administration of ketamine, norketamine, or a derivative thereof,or any of the compounds described herein (e.g., a compound according toany one of formulas (I), (I-A), (I-B), and (II), or any of the compoundsdescribed in Tables A-D, or in any of the Examples provided herein), ora pharmaceutically acceptable salt thereof, comprising the steps offormulating ketamine, norketamine, or a derivative thereof, or any ofthe compounds described herein (e.g., a compound according to any one offormulas (I), (I-A), (I-B), and (II), or any of the compounds describedin Tables A-D, or in any of the Examples provided herein), or apharmaceutically acceptable salt thereof, into a tablet, e.g.,single-layer tablet, that provides a steady release of a therapeuticallyeffective concentration of the ketamine, norketamine, or derivativethereof, or any of the compounds described herein (e.g., a compoundaccording to any one of formulas (I), (I-A), (I-B), and (II), or any ofthe compounds described in Tables A-D, or in any of the Examplesprovided herein), or a pharmaceutically acceptable salt thereof, from anoral tablet over a complete release period without neurologically toxicspikes, e.g., no sedative or psychotomimetic toxic spikes in plasmaketamine concentration, to produce a neuro-attenuating ketamine (NAKET),neuro-attenuating norketamine (NANKET), and/or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, tablet composition, e.g., single-layer tabletcomposition; and orally administering the tablet composition to asubject, such that the NAKET, NANKET, and/or any of the compoundsdescribed herein (e.g., a compound according to any one of formulas (I),(I-A), (I-B), and (II), or any of the compounds described in Tables A-D,or in any of the Examples provided herein), or a pharmaceuticallyacceptable salt thereof, provides a continuous therapeutically effectiveconcentration of ketamine, norketamine, or a derivative thereof, or anyof the compounds described herein (e.g., a compound according to any oneof formulas (I), (I-A), (I-B), and (II), or any of the compoundsdescribed in Tables A-D, or in any of the Examples provided herein), ora pharmaceutically acceptable salt thereof, to the subject.

In certain embodiments of the invention, the subject is a mammal.

In certain embodiments of the invention, the mammal is a human.

In another embodiment, the present invention provides a method offormulating ketamine, norketamine, or a derivative thereof, or any ofthe compounds described herein (e.g., a compound according to any one offormulas (I), (I-A), (I-B), and (II), or any of the compounds describedin Tables A-D, or in any of the Examples provided herein), or apharmaceutically acceptable salt thereof, to ensure the steady releaseof a therapeutically effective concentration of the ketamine,norketamine, or a derivative thereof, or any of the compounds describedherein (e.g., a compound according to any one of formulas (I), (I-A),(I-B), and (II), or any of the compounds described in Tables A-D, or inany of the Examples provided herein), or a pharmaceutically acceptablesalt thereof, from an oral tablet without neurologically toxic spikes,e.g., sedative or psychotomimetic toxic spikes, in plasma ketamineconcentration. In a particular embodiment, the method comprises the stepof combining (i) a water-insoluble neutrally charged non-ionic matrix;(ii) a polymer carrying one or more negatively charged groups; and (iii)ketamine or a derivative thereof, to produce a neuro-attenuatingketamine orally administered tablet composition, e.g., single-layer. Ina particular embodiment, the method comprises the step of combining (i)a water-insoluble neutrally charged non-ionic matrix; (ii) a polymercarrying one or more negatively charged groups; and (iii) norketamine ora derivative thereof, to produce a neuro-attenuating norketamine orallyadministered tablet composition, e.g., single-layer. In a particularembodiment, the method comprises the step of combining (i) awater-insoluble neutrally charged non-ionic matrix; (ii) a polymercarrying one or more negatively charged groups; and (iii) any of thecompounds described herein (e.g., a compound according to any one offormulas (I), (I-A), (I-B), and (II), or any of the compounds describedin Tables A-D, or in any of the Examples provided herein), or apharmaceutically acceptable salt thereof, to produce a neuro-attenuatingorally administered tablet composition, e.g., a single-layer tablet. Inanother particular embodiment, the method comprises the step ofcombining (i) polyethylene oxide (PEO), e.g., MW about 2,000 to about7,000 KDa, with HPMC, and (ii) ketamine or a derivative thereof, toproduce a neuro-attenuating ketamine orally administered tabletcomposition, e.g., single-layer. In another particular embodiment, themethod comprises the step of combining (i) polyethylene oxide (PEO),e.g., MW about 2,000 to about 7,000 KDa, with HPMC, and (ii) norketamineor a derivative thereof, to produce a neuro-attenuating norketamineorally administered tablet composition, e.g., single-layer. In specificembodiments, wherein the method comprises the step of combiningpolyethylene oxide (PEO) with HPMC, and ketamine, the tablet compositionmay further comprise polyethylene glycol (PEG), e.g., PEG 8K, a polymercarrying one or more negatively charged groups, e.g., polyacrylic acidand/or may be further subjected to heating/annealing, e.g., extrusionconditions. In another particular embodiment, the method comprises thestep of combining (i) polyethylene oxide (PEO), e.g., MW about 2,000 toabout 7,000 KDa, with HPMC, and (ii) any of the compounds describedherein (e.g., a compound according to any one of formulas (I), (I-A),(I-B), and (II), or any of the compounds described in Tables A-D, or inany of the Examples provided herein), or a pharmaceutically acceptablesalt thereof, to produce a neuro-attenuating orally administered tabletcomposition, e.g., single-layer. In certain embodiments, theformulations of the invention may be administered in combination withother active therapeutic agents, e.g., opioids to reduce pain. Inparticular embodiments, the formulations of the present invention serveto reduce the amount of opioids necessary to treat a patient.

In certain embodiments, the formulations of the invention are notadministered in combination with other active therapeutic agents.

In certain embodiments, the formulations of the invention may beadministered in combination with another formulation of ketamine, e.g.,a fast release formulation of ketamine.

In another embodiment, the present invention provides a method offormulating ketamine, norketamine, or a derivative thereof, or any ofthe compounds described herein (e.g., a compound according to any one offormulas (I), (I-A), (I-B), and (II), or any of the compounds describedin Tables A-D, or in any of the Examples provided herein), or apharmaceutically acceptable salt thereof, to ensure the steady releaseof a therapeutically effective concentration of the ketamine,norketamine, or a derivative thereof, or any of the compounds describedherein (e.g., a compound according to any one of formulas (I), (I-A),(I-B), and (II), or any of the compounds described in Tables A-D, or inany of the Examples provided herein), or a pharmaceutically acceptablesalt thereof, from an oral tablet without sedative or psychotomimetictoxic spikes in plasma concentration of the ketamine, norketamine, orderivative thereof, or any of the compounds described herein (e.g., acompound according to any one of formulas (I), (I-A), (I-B), and (II),or any of the compounds described in Tables A-D, or in any of theExamples provided herein), or a pharmaceutically acceptable saltthereof. The method comprises formulation of ketamine, norketamine, or aderivative thereof, or any of the compounds described herein (e.g., acompound according to any one of formulas (I), (I-A), (I-B), and (II),or any of the compounds described in Tables A-D, or in any of theExamples provided herein), or a pharmaceutically acceptable saltthereof, in an osmotic controlled release tablet. In these formulationsthe single core layer containing ketamine, norketamine, or a derivativethereof, or any of the compounds described herein (e.g., a compoundaccording to any one of formulas (I), (I-A), (I-B), and (II), or any ofthe compounds described in Tables A-D, or in any of the Examplesprovided herein), or a pharmaceutically acceptable salt thereof, issurrounded by semi-permeable membrane with or without drug deliveryorifice. In certain embodiments, combination with the novel andinventive pharmaceutical compositions (e.g., the NAKET or NANKET tabletformulations or the pharmaceutical compositions comprising any of thecompounds described herein (e.g., a compound according to any one offormulas (I), (I-A), (I-B), and (II), or any of the compounds describedin Tables A-D, or in any of the Examples provided herein), or apharmaceutically acceptable salt thereof) of the present invention andosmotic asymmetric-membrane technology or AMT (e.g., technology directedto a single-layer tablet coated with an insoluble, asymmetricmicroporous membrane produced by controlled phase separation) may beused to produce formulations useful in the methods and kits describedherein.

VI. Exemplification

The present invention is illustrated by the following examples, whichare not intended to be limiting in any way.

Example 1

Formulation of the Controlled Release Ketamine Tablet Using a MatrixBased on HPMC and Starch

1, by dry granulation using a controlled release matrix based on acombination of hydroxypropyl methyl cellulose (HPMC) Methocel KM100 CRand pre-gelatinized starch Starch 1500. Methocel, Starch 1500, ketamineand Cab-o-Sil (colloidal silicon dioxide) were coarsely mixed and passedthrough a 40-mesh screen to break-up agglomerates. Microcrystallinecellulose was then added and the mixture blended in a 100 ml tubeblender for 15 minutes at 200 rev/min. The full composition of ketaminetablet KTM-1 is presented in Table 1.

After blending, magnesium stearate was added and blended for additional3 minutes. The 200 mg convex-shaped tablets containing 20 mg of ketaminewere compressed using a TDP tablet press and 9 mm dye. By applying acompression force of 8 kN, the tablets of the hardness in the range13-15 kP were generated. The tablet dissolution was carried out in aType II dissolution apparatus (paddle) (Distek Premiere 5100 DissolutionSystem, Distek Inc., North Brunswick, USA) at 100 rpm, 37° C., using1×PBS buffer, pH=6.8 as an immersion media. Three tablets per batch weretested.

At predetermined time intervals, 1 ml samples were withdrawn (notreplaced), filtered and assayed. The amount of ketamine released wasmeasured by HPLC using an Agilent 1100 setup and UV detection at 210 nm.A 20 microliter sample volume was injected onto a Zorbax SB-Phenylcolumn, 4.6×150 mm, 5 microns, using as the mobile phase a mixture of70% ammonium acetate (10 mM) and 30% acetonitrile; flow rate 1.5 ml/min;column temperature 40° C. Solutions of known concentrations of ketaminewere used to calculate the amount of drug released.

The method was linear in the range of concentration 0.001 to 0.5 mg/ml.Drug release was independent of the pH of the immersion media. A releaseat pH 1 and 6.8 displayed similar profiles. At 10 h time point, about92.5% of ketamine has been released.

Table 1 (FIG. 1) Ketamine Tablet Compositions Based on the HPMC Matrix.Ingredient Manufacturer′s Brand KTM-1 KTM-2 KTM-3 HPMC Methocel  50.0% 41.7%  45.5% KM100 CR Pre-gelatinized Starch 1500  19.0%  15.8%  17.3%Starch Microcrystalline Avicel PH-200  20.0%  16.7%  18.2% CelluloseSilica Cabosil M-5P   0.5%   0.4%   0.5% Ketamine Ketamine  10.0%   8.3%  9.1% Hydrochloride Polyacrylic Acid Carbopol 974 NF   0.0%  16.7%  9.1% Mg Stearate Spectrum   0.5%   0.4%   0.5% Total 100%   100%  100%  

Example 2

Formulation of the Neuro-Attenuating Ketamine Tablet Using HPMC andPolyacrylate

Ketamine was formulated into a tablet form by dry granulation followingthe general procedure as described in the Example 1. The controlformulation KTM-1 presented in Table 1 was supplemented by addingpolyacrylic acid, Carbopol 974 NF (Noveon), for a total content of 16.7%and 9.1% to make compositions KTM-2 and KTM-3, respectively (See Table1).

Consequently, this addition led to a surprisingly dramatic slowing downof the release (FIG. 1 ). Compared to the KTM-1, at the 10 hour timepoint KTM-2 showed only 49% of the drug was released; and at 24 hours62% of the ketamine was released.

Moreover, reducing the level of Carbopol (i.e., polyacrylic acid) toabout 9% in KTM-3 generated a release profile that matched closely to awindow of 24-h, for once-a-day ketamine applications. The amount of thedrug released at 24 h was about 82%. Composition KTM-3 was consideredfor development given typical acceleration of the release rate in vivo.

Example 3

Formulation of Sample 36 Hour Neuro-Attenuating Ketamine Tablet withKollidon SR

Based on the potential for additional in situ electrostatic interactionsof ketamine with the polymer matrix to retain the drug, apolyvinylacetate/povidone based polymer (Kollidon® SR) was elected. Itconsists of 80% Polyvinylacetate and 19% Povidone in a physical mixture,stabilized with 0.8% sodium lauryl sulfate and 0.2% colloidal silica.Kollidon SR possesses good compressibility and typically displays drugrelease profile independent of the dissolution medium (pH and salt/ioncontent).

A 200 mg tablets containing 20 mg of ketamine was produced usingprotocol similar to Example 2, with a mixture of Kollidon SR andmicrocrystalline cellulose to produce formulation KTM-11. The tabletcomposition is presented in the Table 2. The tablets displayed a goodhardness, in the range of 15-20 kP, and released 56% of the drug at 10hours and 78% at 24 hours, with full release expected to be between 36and 48 hour time points (FIG. 2 ).

Addition of about 10% of lactose (formulation KTM-4) led to fasterrelease, about 72% of the drug in 10 hours, and about 95% in 24 hours.

TABLE 2 Ketamine Tablet Compositions Based on the Kollidon Matrix.Ingredient Manufacturer′s Brand KTM-11 KTM-4 Kollidon Kollidon SR  66.8% 60.0% Microcrystalline Avicel PH-200  22.3%  19.0% Cellulose KetamineKetamine Hydrochloride   9.9%  10.0% Lactose Lactopress 250   0%   10.0% Mg Stearate Spectrum   0.5%   1.0% Total 100%   100%  

Example 4

Lipophilic Matrix Tablet Formulation of the Neuro-Attenuating KetamineUsing Glyceryl Behenate

Glyceryl behenate (Compritol®, 888 ATO, Gattefosse) is a hydrophobicfatty acid ester of glycerol, which may be used as a lipophilicmatrix-forming agent in the manufacture of sustained-release tablets.When compressed, it forms an insoluble network structure, allowingdissolution fluid to gradually penetrate and subsequentdiffusion-controlled drug release to occur through matrix channels andpores. Unlike hydrophilic matrix systems, which utilize swellablepolymers such as HPMC and rely on diffusion and erosion mechanisms, drugrelease from insoluble matrix systems is dependent on the rate andextent of water permeation and the aqueous solubility of the drugembedded in the matrix.

The 200 mg tablets containing 20 mg of ketamine were produced using amixture of Compritol (20%), dibasic calcium phosphate and lactose(formulation KTM-9). The tablets display a relatively low hardness, inthe range of 6-7 kP, and release about 92% of the drug in 8 hour.Addition of about 10% of polyacrylic acid (formulation KTM-12) leads toslowed release, about 65% at 10 hour and about 92% at 24 hour timepoints.

Example 5

Formulation of the Controlled Release Ketamine Tablet Using a MatrixBased on PEO

Polyethylene oxide (PEO) is a known ingredient for the extended releasesolid dose forms. It has been shown to display similar formulationfunctional properties to HPMC. PEO-based formulations may be produced bydry granulation as well by melt extrusion, producing solid dispersionsof the active pharmaceutical ingredients. As a thermoplastic polymer,PEO has glass transition temperatures in the range of 80-100° C.(depending on the molecular weight; the grade used for extended releaseformulation are typically within 900-7,000 KDa M average molecularweight) and could be melted during the extrusion process, solubilizingthe drugs.

The 220 mg tablets containing 20 mg of ketamine were produced by drygranulation using a mixture of two different grades of PEO (MW about2,000 and about 7,000 KDa), in combination with HPMC (formulationsKTM-13, 14, respectively). The release properties were explored uponchanging the following additional variables in the composition andprocessing: i) Molecular weight of PEO; (ii) Addition of polyacrylicacid as a prototypical acidic ingredient, described herein as apotential to slow down the release (formulation KTM-15); (iii) Additionof the high molecular weight PEG 8K (formulation KTM-16); (iv) annealingof the tablets for 20 min in the oven at 120° C. to mimic the mechanicalproperties achieved by extrusion (formulation KTM-15a).

The full compositions of tablets KTM-13-16 is presented in Table 3.

The tablets displayed a relatively high hardness, in the range of 15-20kP that increases upon annealing to 30-35 kP, indicative of acquiringtamper-resistance properties enabled by improved crush resistance. Weobserved little differentiation in the release properties upon changingany of the above variables, with about 90-100% release achieved in about12 h of time.

TABLE 3 Ketamine Tablet Compositions Based on the PEO Matrix Manufact.Ingredient Brand KTM-13 KTM-14 KTM-15 KTM-16 PEO, Colorcon,  67.9%  0.0%  60.3%  52.7% MW = 2M N60K PEO, Colorcon,   0.0%  67.9%   0.0%  0.0% MW = 7M WSR-303 LEO HPMC Methocel  22.6%  22.6%  22.6%  22.6%KM100 CR PEG, 8K Spectrum   0.0%   0.0%   0.0%  15.2% Ketamine Ketamine  9.1%   8.3%   9.1%   9.1% Hydrochloride Polyacrylic Carbopol 974  0.0%   0.0%   7.6%   0.0% Acid NF Mg Spectrum   0.4%   0.4%   0.4%  0.4% Stearate Total 100.0% 100.0% 100.0% 100.0%

Example 6

In Vivo Performance of the Neuro-Attenuating Ketamine TabletFormulations of the Present Invention

Pharmacokinetics of the KTM-2 formulation described herein was tested inbeagle dogs. In particular, one tablet of the formulation KTM-2 wasadministered orally with 10 ml of water to one male and one female dogthat had been fasted for 12 h before administration.

The blood samples were drawn at time points 0, 0.5, 1, 2, 4, 8, and 24h.

Ketamine and norketamine were quantified in plasma using LC/MS/MS method(Agilent 1200/AB SCIEX 4000 QTRAP instrumental setup) following thegeneral procedure as described by Nettoa et al. (Biomed. Chromatogr.,2011); using the related analytical standards of ketamine andnorketamine purchased from Sigma-Aldrich.

The dogs tolerated the drug well with no observed physiological orbehavioral side effects. The study showed a steady release of the drugfrom the matrix that is maintained for a 24 h period, with a totalketamine/norketamine concentration being within therapeutically relevantlevels and no detected concentration spikes. A graph of the combinedketamine/norketamine plasma concentrations (in two dogs) vs. time isshown in FIG. 5 .

This experiment confirms good in vitro-vivo correlations and validatesthe general pathways outlined herein related to the development andpreparation of formulations of the present invention, e.g., suitable forhuman clinical trials.

Example 7

Enantioselective Synthesis of Deuterated Norketamine

The synthesis is conducted following a reaction sequence as described byBierman et al., 2011 for non-deuterated material (Scheme 1). Thestarting 2-chlorophenyl-1-cyclohexene-d₁₀ 1 is prepared fromcycloxene-d₁₂ that is obtained by dehydration of a commerciallyavailable cyclohexanol-d₁₀ (CDN Isotopes). In the first step,2-chlorophenyl-1-cyclohexene is dihydroxylated by osmium tetraoxidemodified with hydroquinine 1,4-phthalazinediyl diether using Sharplessasymmetric synthesis (Kolb, 1994) to yield(−)-(1S,2S)-1-(2-chlorophenyl)cyclohexane-1,2-diol 2 in 90% yield andwith 85% ee after crystallization from n-hexane. In the second step,compound 2 is converted to(−)-(1S,2S)-1-amino-1-(2-chlorophenyl)cyclohexane-2-ol 3, with 95% eeand 79% yield by the Ritter transformation (Senanayake et al., 1996). Inthe third step, a modified Jones oxidation (Yang et al., 1985) of 3leads to (S)-2-amino-2-(2-chlorophenyl)cyclohexanone ((+)-S-norketamine)4 (Parcell, 1981). The chiral purity is ee 99% determined by chiralHPLC. The specific rotation of the free S-norketamine base is measuredto be [a]D+3.2° (c=2, EtOH). NMR and MS-spectroscopy confirms theidentity of the products.

Example 8

Nonstereoselective Synthesis of Deuterated Norketamine

The synthesis was conducted following a general reaction sequence asdescribed by Parcell, 1981 (Scheme 2). In the first step,o-chlorobenzonitrile is reacted with cyclopentyl magnesium bromide(obtained by bromination of the commercially available cyclopentane-d₁₀to give cyclopentane bromide-d₉ 6 and then by Grignard reaction) to givedeuterated 1-chlorophenyl-cyclopentyl ketone 7, followed byalpha-bromination of the ketone to give 8, and then reaction withammonia to form an alpha-hydroxy imine1-hydroxycyclopentyl-(1-chlorophenyl)-ketone-N-methylimine 9. Thermalrearrangement with ring expansion of 9 leads to racemic norketamine 10with overall yield of 70%. NMR and MS-spectroscopy confirmed theidentity of the products.

Example 9

Synthesis of Deuterated Norketamine by Deuterium Exchange

The hydrogen atoms or me methylene group adjacent to the carbonyl groupare known to undergo a facile proton exchange. Consequently, deuteriumexchange in norketamine may be investigated by heating in a heavy watersolution (0.01 M) at 80° C. in presence of NaOD (0.1 M) and followingthe reaction by proton NMR. The progress of the reaction is followed byalterations in the multiplet signal at ca. 2.3 ppm that corresponds tothe carbonyl methylene group. In 30 minutes, a simplification of thefine structure is observed along with a decrease of the signal integralintensity consistent with the lost of two proton. After heating at80-90° C. for 24 h, an extent of the deuteration is 70-80%. Prolongedreaction time past 24 h didn't result in the increased yields andaccumulated degradation impurities. In optimized conditions, thedeuterium exchange is conducted in the mixtures of deuterated methanolor ethanol with deuterated water, with alcohol fraction constituting40-90% of the mixture. In these conditions, even at room temperature thehydrogen-deuterium exchange is found to be very rapid and complete—theproton NMR spectra recorded immediately after addition of the base showsa complete disappearance of the target protons and conservation of therest of the spectrum. A deuterated norketamine 11 is obtained bychloroform extraction of the basic reaction mixture in a quantitativeyield after evaporation of the solvent (Scheme 3). Deuteratednorketamine is stable towards hydrogen exchange at neutral and acidicpH. We observed no changes in the NMR spectra of 11 in deuteratedchloroform upon treating the solution in situ with small amounts ofwater, hydrochloric or acetic acid.

In an alternative procedure, norketamine hydrochloride (20 mg) wasplaced in a 5 ml screw-cap vial and dissolved in 1 ml of CD₃OD withmagnetic stirring. To this solution, D₂O (0.2 ml) was added followed by40% NaOD in deuterated water (0.1 ml). The reaction mixture was stirredat ambient temperature for 10 min and evaporated to dryness at reducedpressure. The residue was treated with D₂O (1 ml) and extracted with 3×2ml of ethyl acetate. After drying the ethyl acetate extract with Na₂SO₄,the solvent was evaporated to yield 18 mg (90%) of the deuteratednorketamine 11 as a white solid. ¹H NMR (CDCl₃) d 7.7 (dd, J=7.8, 1.7Hz, 1H), 7.4-7.3 (m, 2H), 7.3-7.2 (m, 1H), 2.8-2.7 (m, 1H), 2.1-2.0 (m,1H), 1.9-1.7 (m, 3H), 1.7-1.6 (m, 1H). LC/MS, m/z 224 (M++1).

Example 10

Nonstereoselective Synthesis of Norketamine 10 Using Cyclohexanone-d₈

Alternative synthesis of the deuterated norketamine compound 11 isconducted using a scheme reported by Sulake et al. (2011) that startswith bromochlorobenzene which is converted into the Grignard reagent inTHF and reacted with commercially available cyclohexanone-d₈ (CDNisotopes) to give 1-(2-chlorophenyl)cyclohexanol. Dehydration ofcyclohexanol with p-TSA in benzene provides1-(2-chlorophenyl)cyclohexene in quantitative yield followed by itsepoxidation with m-chloroperoxy benzoic acid (m-CPBA) that leads to1-(2-chlorophenyl)-7-oxabicyclo[4.1.0]heptane. Regioselective ringopening of epoxide with HBr provides bromohydroxy intermediate that isfollowed by oxidation with pyridinium chlorochromate (PCC) in DCMleading to the related keto-compound. Nucleophilic exchange of thebromide with and azide group and reduction of azide using Staudingercondition gives norketamine compound 11 in overall 60% yield.

Example 11

Metabolic Activity of the Deuterated Nor-Ketamines In Vitro

Deuterated norketamines 11 and 12 have the below structures.

Deuterated norketamine 11 (10 microl of 2 microM solution) was incubatedin 200 microliter of the medium that consists of 100 mg rat livermicrosomes, NADPH regenerating system (1 mM NADP, 1 unit/ml ofisocitrate dehydrogenase, 5 mM isocitric acid, 5 mM magnesium chloride),and 25 mM of phosphate buffer (pH 7.4). The reaction is terminated atdifferent time points (0 to 60 min) by the addition of 300 microl ofacetonitrile. For the analyses of metabolites, the precipitated saltsand proteins are spun out on a centrifuge, the residual solution dilutedwith 300 microl of water and injected into the LC/MS (Agilent 1200system interfaced with an ABS Sciex 4000 QTRAP LC/MS/MS MassSpectrometer).

Metabolic transformation of norketamine yields multiple products relatedto hydroxylation at different position of the cyclohexyl and aryl group,as well as dehydrogenation to dehydro-norketamine, some of which areeliminated in vivo as glucuronides. The metabolic stability ofnorketamine may be estimated by evaluating the rate of disappearance ofthe main peak.

We observed an about 80% increase in the half-life for compound 11compared to the non-deuterated norketamine. The half-life of thetetra-deuterated norketamine with deuterium substitutions at the phenylring, compound 12, was found to be similar to the non-deuteratednorketamine. The data are shown in the FIG. 6 . The collective kineticdeuterium isotope effect (the reaction rate decrease for deuterated vs.non-deuterated analogue) is expected to be more substantial, at >100%for the fully deuterated cyclohexanone material.

Example 12

Pharmacokinetics of the Deuterated Nor-Ketamines In Vivo

Pharmacokinetics of the deuterated norketamines is studied in rats. Agroups of 3 Wistar female rats (200-250 g) with surgically insertedjugular vein catheter (Charles River, Andover, Mass.) are fasted for 12h and then given a mixture of 0.8 mg/kg each of norketamine anddeuterated norketamine compound 11 solution by an injection into thetail vein. The blood is drawn at time points 0, 15, 30, 60 min, and 2,4, 6, 8, and 24 h and resulting plasma analyzed concurrently fornorketamine and deuterated norketamine compound 11 using LC/MSspectroscopy (limit of quantitation ca. 1 ng/ml for each analyte). Theexperimental data are shown in the FIG. 7 . The terminal half-lives arecalculated by fitting the data points using a WinNonLin softwarepackage. The terminal half-life T_(1/2), for norketamine is found to beat 2.07 h and for the bis-deuterated compound 11 at 2.83 h, ca., 40%increase indicative of a significantly slower metabolic transformationrendered by deuterium substitution on compound 11.

We expect further prolongation of the terminal half-life for the fullydeuterated compound 10 to over 3 h consistent with slower elimination ofnorketamine due to the kinetic deuterium isotope effects relatedmetabolic oxidation to hydroxylated products.

Example 13

NMDA Receptor Activity of the Deuterated Norketamine

We measured electrophysiological functional response to the deuteratedcompound 10 by the patch clamp method in cultural hippocampal ratneurons to confirm that NMDA receptor activity is not altered bydeuterium substitution. We use racemic ketamine as a reference standardthat displays a receptor inhibition with IC₅₀ of 2.2 μM that is withinthe range of the literature data. Norketamine is a weaker inhibitor withIC₅₀ of 14.7 μM, again in agreement with the previously reported data.Bis-deuterated norketamine compound 11 has IC₅₀ of 25.9 μM in thisassay, very close to the non-deuterated norketamine.

We expect that fully deuterated compound 10 will have a full functionalactivity in the concentration range similar to the bis-deuteratednorketamine compound 10 and non-deuterated norketamine.

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INCORPORATION BY REFERENCE

The entire contents of all patents, published patent applications andother disclosures cited herein are hereby expressly incorporated hereinin their entireties by reference.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures described herein. Such equivalents were consideredto be within the scope of this invention and are covered by thefollowing claims. Moreover, any numerical or alphabetical rangesprovided herein are intended to include both the upper and lower valueof those ranges. In addition, any listing or grouping is intended, atleast in one embodiment, to represent a shorthand or convenient mannerof listing independent embodiments (e.g., such as particular painindications); as such, each member of the list should be considered aseparate embodiment.

What is claimed is:
 1. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein each of X₁, X₂,X₃, and X₄ is hydrogen; X₅, X₆, X₇, X₈, X₉, X₁₀, X₁₁, X₁₂, X₁₃, and X₁₄are each independently selected from the group consisting of hydrogenand deuterium, and wherein at least one of X₅, X₆, X₇, X₈, X₉, X₁₀, X₁₁,and X₁₂ is deuterium.
 2. The pharmaceutical composition of claim 1,wherein X₁₃ and X₁₄ are hydrogen.
 3. The pharmaceutical composition ofclaim 1, wherein the compound has a structure


4. The pharmaceutical composition of claim 1, wherein the compound has astructure


5. The pharmaceutical composition of claim 2, wherein each deuterium hasa deuterium incorporation of at least 52.5%.
 6. The pharmaceuticalcomposition of claim 2, wherein each deuterium has a deuteriumincorporation of at least 75%.
 7. The pharmaceutical composition ofclaim 2, wherein each deuterium has a deuterium incorporation of atleast 90%.
 8. The pharmaceutical composition of claim 2, wherein eachdeuterium has a deuterium incorporation of at least 95%.
 9. Thepharmaceutical composition of claim 3, wherein each deuterium has adeuterium incorporation of at least 52.5%.
 10. The pharmaceuticalcomposition of claim 3, wherein each deuterium has a deuteriumincorporation of at least 75%.
 11. The pharmaceutical composition ofclaim 3, wherein each deuterium has a deuterium incorporation of atleast 90%.
 12. The pharmaceutical composition of claim 3, wherein eachdeuterium has a deuterium incorporation of at least 95%.
 13. Thepharmaceutical composition of claim 4, wherein each deuterium has adeuterium incorporation of at least 52.5%.
 14. The pharmaceuticalcomposition of claim 4, wherein each deuterium has a deuteriumincorporation of at least 75%.
 15. The pharmaceutical composition ofclaim 7, wherein each deuterium has a deuterium incorporation of atleast 90%.
 16. The pharmaceutical composition of claim 4, wherein eachdeuterium has a deuterium incorporation of at least 95%.